Steroidal Compositions

ABSTRACT

Provided herein are steroid containing compositions suitable for providing therapeutically effective amounts of at least one steroid to individuals. Also provided herein are compositions comprising testosterone and/or testosterone derivatives suitable for providing therapeutically effective and safe amounts of testosterone over periods of time. Further provided are methods of treating andro- and/or testosterone deficiency in individuals by administering to the individuals compositions described herein.

PRIORITY DATA

This application is a continuation of U.S. patent application Ser. No.12/350,930, filed Jan. 8, 2009 which is incorporated herein by referencein its entirety.

BACKGROUND OF THE INVENTION

Testosterone is an androgenic compound crucial for human health. Certainembodiments of the invention described herein generally relate tocompositions for the administration of testosterone, testosteroneanalogs, other steroids and related compounds.

SUMMARY OF THE INVENTION

Provided in certain embodiments herein is a delayed release oral dosageform comprising a therapeutically effective amount of one or moretestosterone alkyl ester and at least one pharmaceutically acceptablecarrier, wherein a single dose of the delayed release oral dosage formprovides a mean plasma C_(max) of testosterone that is at least 5%, atleast 10% or at least 15% lower than the mean plasma C_(max) oftestosterone that is provided by a single dose of an immediate releaseoral dosage form having an identical amount of the testosterone alkylester. In some embodiments, provided herein is a delayed release oraldosage form, wherein a single dose of the delayed release oral dosageform provides a mean plasma C_(max) of testosterone alkyl ester that isat least 5%, at least 10% or at least 15% lower than the mean plasmaC_(max), of testosterone alkyl ester that is provided by a single doseof an immediate release oral dosage form having an identical amount ofthe testosterone alkyl ester. In certain embodiments, a single dose ofthe delayed release oral dosage form described herein provides a meanplasma C_(max) of that is at least 5% lower than the mean plasma C_(max)of dihydrotestosterone provided by a single dose of an immediate releaseoral dosage form having an identical amount of the testosterone alkylester. In some embodiments, a delayed release oral dosage form describedherein provides a mean plasma C_(max) at steady state of testosteronealkyl ester that is at least 5%, at least 10% or at least 15% lower thanthe mean plasma C_(max) of testosterone alkyl ester at steady stateprovided by an immediate release oral dosage form having an identicalamount of the testosterone alkyl ester. In certain embodiments, adelayed release oral dosage form described herein provides a fluctuationindex of testosterone at steady state that is at least 5%, or at least10% lower than a fluctuation index of testosterone at steady state of animmediate release oral dosage form having an identical amount of thetestosterone alkyl ester. In some embodiments, a delayed release oraldosage form described herein provides a fluctuation index oftestosterone alkyl ester at steady state that is at least 5%, or atleast 10% lower than a fluctuation index of testosterone alkyl ester atsteady state of an immediate release oral dosage form having anidentical amount of the testosterone alkyl ester. In some embodiments, asingle dose of the delayed release oral dosage form provides a meanplasma concentration of testosterone provided 1 hour after oraladministration of the delayed release oral dosage form that is at least20% lower than a mean plasma concentration of testosterone provided 1hour after oral administration of a single dose of an immediate releaseoral dosage form having an identical amount of the testosterone alkylester.

Provided in certain embodiments herein is a pharmaceutical compositioncomprising a therapeutically effective amount of one or moretestosterone alkyl ester and at least one pharmaceutically acceptablecarrier. In some embodiments, a single dose of a pharmaceuticalcomposition described herein provides a mean plasma C_(max) oftestosterone that is about 15 ng/mL or less; or about 19 ng/mL or lessupon oral administration. In certain embodiments, a single dose of apharmaceutical composition described herein provides a mean plasmaC_(max) of dihydrotestosterone that is about 4.5 ng/mL, or about 3.6ng/mL or less upon oral administration. In some embodiments, apharmaceutical composition described herein provides a testosterone meanplasma C_(max) at steady state of about 1300 ng/dL or less. In certainembodiments, a pharmaceutical composition described herein provides atestosterone mean plasma C_(min) at steady state of about 200 ng/dL ormore. In some embodiments a pharmaceutical composition provides withadministration to an individual a ratio of the testosterone equivalentdose from the alkyl ester, to a mean steady state testosterone C_(max),the ratio being about 500×10⁶ mL or less. In certain embodiments, thedifference between the mean plasma C_(max) of testosterone at steadystate and mean plasma C_(min) of testosterone at steady state providedby a pharmaceutical composition described herein is about 11 ng/mL orless, or about 16 ng/mL or less. In some embodiments, the differencebetween the mean plasma C_(max) at steady state and mean plasma C_(min)at steady state of testosterone alkyl ester provided by a pharmaceuticalcomposition described herein is about 275 ng/mL or less; or about 200ng/mL or less. In certain embodiments, a single dose of a pharmaceuticalcomposition described herein provides a mean plasma concentration oftestosterone after 1 hour that is about 150 ng/dL or less upon oraladministration. In some embodiments, a single dose of a pharmaceuticalcomposition described herein provides a mean plasma concentration oftestosterone after 2 hours that is about 500 ng/dL or less upon oraladministration.

In certain embodiments, a pharmaceutical composition described hereinreleases about 50% or less of the testosterone alkyl ester after 1 hourand/or about 80% or less of the testosterone alkyl ester after about 30minutes in an aqueous medium. In some embodiments, a pharmaceuticalcomposition described herein releases about 20% or less of thetestosterone alkyl ester after 30 minutes in an aqueous medium. Incertain embodiments, a pharmaceutical composition described hereinreleases less than 95% of the testosterone alkyl ester after 3 hours inan aqueous medium. In some embodiments, a pharmaceutical compositiondescribed herein releases more than 80% of the testosterone alkyl esterwithin 12 hours in an aqueous medium. In some instances, the aqueousmedium is present in a USP Type-II (paddle) apparatus with conditions at37±0.5° C. and at 100 rpm. In more specific instances, the aqueousmedium is about 1 L of DI water having 8% w/v of Triton X-100.

In certain embodiments, described herein is a delayed release oraldosage form comprising a testosterone alkyl ester (e.g., testosteronealkyl ester formulated in solid PEG). In some embodiments, apharmaceutical composition described herein is a delayed release oraldosage form. In certain embodiments, the delayed release oral dosageform is formulated in any suitable manner. In some embodiments, a singledose of a delayed release oral dosage form described herein provides amean plasma C_(max) of testosterone that is at least about 5%, at least10% or at least 15% lower than the mean plasma C_(max) of testosteronethat is provided by a single dose of an immediate release oral dosageform having an identical amount of the testosterone alkyl ester. Incertain embodiments, a single dose of a delayed release oral dosage formdescribed herein provides a mean plasma C_(max) of the testosteronealkyl ester that is at least about 5%, at least 10% or at least 15%lower than the mean plasma C_(max) of testosterone alkyl ester that isprovided by a single dose of an immediate release oral dosage formhaving an identical amount of the testosterone alkyl ester. In someembodiments, a single dose of a delayed release oral dosage formdescribed herein provides a mean plasma C_(max) of that is at least 5%lower than the mean plasma C_(max) of dihydrotestosterone provided by asingle dose of an immediate release oral dosage form having an identicalamount of the testosterone alkyl ester. In certain embodiments, adelayed release oral dosage form described herein provides a mean plasmaC_(max) at steady state of testosterone alkyl ester that is at leastabout 5%, at least 10% or at least 15% lower than the mean plasmaC_(max) of testosterone alkyl ester at steady state provided by animmediate release oral dosage form having an identical amount of thetestosterone alkyl ester. In some embodiments, a delayed release oraldosage form described herein provides a fluctuation index oftestosterone at steady state that is at least 10% lower than afluctuation index of testosterone at steady state of an immediaterelease oral dosage form having an identical amount of the testosteronealkyl ester. In certain embodiments, a delayed release oral dosage formdescribed herein provides a fluctuation index of testosterone alkylester at steady state that is at least 10% lower than a fluctuationindex of testosterone alkyl ester at steady state of an immediaterelease oral dosage form having an identical amount of the testosteronealkyl ester. In some embodiments, a single dose of a delayed releaseoral dosage form described herein provides a mean plasma concentrationof testosterone provided 1 hour after oral administration of the delayedrelease oral dosage form that is at least 20% lower than a mean plasmaconcentration of testosterone provided 1 hour after oral administrationof a single dose of an immediate release oral dosage form having anidentical amount of the testosterone alkyl ester.

In some embodiments, the one or more testosterone alkyl ester providedin any pharmaceutical composition or oral dosage form described hereinis or comprises testosterone undecanoate. In certain embodiments, anypharmaceutical composition or oral dosage form described hereincomprises about 10 mg to about 400 mg, or about 10 mg to about 1000 mgof testosterone alkyl ester. In some embodiments, any pharmaceuticalcomposition or oral dosage form described herein comprises about 10 mgto about 300 mg of testosterone alkyl ester. In certain embodiments, anypharmaceutical composition or oral dosage form described hereincomprises about 10 mg to about 240 mg of testosterone alkyl ester. Insome embodiments, any pharmaceutical composition or oral dosage formdescribed herein comprises about 10 mg to about 150 mg of testosteronealkyl ester. In some embodiments, any pharmaceutical composition or oraldosage form described herein comprises about 120 mg of testosteronealkyl ester.

In certain embodiments, the at least one pharmaceutically acceptablecarrier of any pharmaceutical composition or oral dosage form describedherein comprises at least one hydrophilic carrier. In some embodiments,the at least one pharmaceutically acceptable carrier of anypharmaceutical composition or oral dosage form described hereincomprises at least one lipophilic carrier. In certain embodiments, theat least one pharmaceutically acceptable carrier of any pharmaceuticalcomposition or oral dosage form described herein comprises at least oneviscosity enhancer or solidifying agent. In some embodiments, the atleast one hydrophilic carrier comprises a hydrophilic triglyceride. Inspecific embodiments, the hydrophilic triglyceride is a polyoxylatedcastor oil, or a polyoxylated hydrogenated castor oil.

Provided in some embodiments herein is a method of treating androgendeficiency in an individual in need thereof by administering to theindividual any oral dosage form or pharmaceutical composition describedherein. In some embodiments, a pharmaceutical composition or oral dosageform described herein is administered b.i.d. In certain embodiments, apharmaceutical composition or oral dosage form described herein isadministered with a meal.

Provided in certain embodiments herein is an oral testosteroneundecanoate therapy that provides to a human in need of androgen therapyby orally delivering to the human a composition comprising atherapeutically effective amount of testosterone undecanoate. In someembodiments, the oral testosterone undecanoate therapy provides in ahuman (e.g., a male human) a mean C_(max) of testosterone that is lessthan about 15 ng/mL; or less than about 19 ng/mL after a singleadministration of the composition. In certain embodiments, the oraltestosterone undecanoate therapy provides to a human (e.g., a malehuman) a mean plasma C_(max) of dihydrotestosterone that is about 3.6ng/mL or less; or about 4.5 ng/mL or less after a single administrationof the composition. In some embodiments, the oral testosteroneundecanoate therapy provides to a human (e.g., a male human) atestosterone mean plasma C_(max) at steady state of about 1300 ng/dL orless. In certain embodiments, the oral testosterone undecanoate therapyprovides to a human (e.g., a male human) a testosterone mean plasmaC_(min) at steady state of about 200 ng/dL or more. In some embodiments,the oral testosterone undecanoate therapy provides to a human (e.g., amale human) a mean C_(max) of testosterone at steady state to dose ratioof about 15 or less. In specific embodiments, the ratio is 15 or less,or 13 or less. In some embodiments provided herein is a pharmaceuticalcomposition that provides with administration to an individual a ratioof a testosterone C₂-C₁₃ alkyl ester dose, in mg, to a mean steady statetestosterone C_(max), in mg/mL, the ratio of testosterone equivalentdose from the testosterone alkyl ester to a mean steady statetestosterone C_(max), the ratio being about 500×10⁶ mL or less (e.g.,with b.i.d. or q.d. administration to an otherwise testosteronedeficient individual). In certain embodiments, the oral testosteroneundecanoate therapy provides to a human (e.g., a male human) adifference between a mean plasma C_(max) of testosterone at steady stateand mean plasma C_(min) of testosterone at steady state of about 11ng/mL or less, or about 16 ng/mL or less. In some embodiments, the oraltestosterone undecanoate therapy provides to a human (e.g., a malehuman) a difference between a mean plasma C_(max) at steady state andmean plasma C_(min) at steady state of testosterone alkyl ester of about200 ng/mL or less; or about 275 ng/mL or less. In certain instances,when a mean plasma concentration is utilized, the value is obtained froma statistically significant population of individuals.

Provided in certain embodiments herein is a pharmaceutical compositioncomprising (i) a therapeutically effective amount of one or moretestosterone C₂-C₁₃ alkyl ester; and (ii) at least one pharmaceuticallyacceptable carrier; the pharmaceutical composition releasing about 80%or less of the testosterone C₂-C₁₃ alkyl ester after 30 minutes in anaqueous medium. In certain instances, the aqueous medium comprises 8%w/v octoxynol-9 in water at about 37° C. In some embodiments, anyaqueous medium described herein is 1 L deionized water comprising 8% w/vTriton X-100 (e.g., octylphenol ethylene oxide condensate; octoxynol-9;t-octylphenoxypolyethoxyethanol; t-oct-C₆H₄—(OCH₂CH₂)_(x)OH, x=9-10; CASNo. 9002-93-1; Triton X-100 was a registered trademark formerly owned byRohm and Haas Co., but now owned by Union Carbide) at 37±0.5° C. andsubjected to a paddle method at 100 rpm and 37±0.5° C. for thedesignated period of time (USP App 2). In some embodiments, thetestosterone C₂-C₁₃ alkyl ester is testosterone undecanoate. In certainembodiments, the pharmaceutical composition comprises about 10 mg toabout 1000 mg of testosterone C₂-C₁₃ alkyl ester.

In some embodiments, a single dose of any pharmaceutical compositionprovided herein provides a mean plasma C_(max) of testosterone that isabout 15 ng/mL or less; or about 19 ng/mL or less upon oraladministration (e.g., to a testosterone deficient individual). Incertain embodiments, a single dose of any pharmaceutical compositionprovided herein provides a mean plasma C_(max) of dihydrotestosteronethat is about 4.5 ng/mL or less; or about 3.6 ng/mL or less upon oraladministration (e.g., to a testosterone deficient individual). In someembodiments, any pharmaceutical composition provided herein provides atestosterone mean plasma C_(max) at steady state of about 1300 ng/dL orless with oral administration (e.g., with b.i.d. or q.d. administrationto an otherwise testosterone deficient individual). In certainembodiments, any pharmaceutical composition provided herein provides atestosterone mean plasma C_(min) at steady state of about 200 ng/dL ormore with oral administration (e.g., with b.i.d. or q.d. administrationto an otherwise testosterone deficient individual). In some embodiments,any pharmaceutical composition provided herein provides withadministration to an individual (e.g., oral administration) a ratio oftestosterone equivalent dose from the testosterone alkyl ester to a meana mean steady state testosterone C_(max), the ratio being about 500×10⁶mL, or less (e.g., with b.i.d. or q.d. administration to an otherwisetestosterone deficient individual).

In some embodiments, the difference between the mean plasma C_(max) oftestosterone at steady state and mean plasma C_(min) of testosterone atsteady state is about 11 ng/mL or less, or about 16 ng/mL or less (e.g.,with b.i.d. or q.d. administration to an otherwise testosteronedeficient individual). In some embodiments, the difference between themean plasma C_(max) at steady state and mean plasma C_(min) at steadystate of testosterone C₂-C₁₃ alkyl ester is about 200 ng/mL or less; orabout 275 ng/mL or less (e.g., with b.i.d. or q.d. administration to anotherwise testosterone deficient individual). In some embodiments, asingle dose of any pharmaceutical composition provided herein provides amean plasma concentration of testosterone after 1 hour that is about 150ng/dL or less upon oral administration. In certain embodiments, a singledose of any pharmaceutical composition provided herein provides a meanplasma concentration of testosterone after 2 hours that is about 500ng/dL or less upon oral administration.

In certain embodiments, the at least one pharmaceutically acceptablecarrier of any pharmaceutical composition provided herein comprises atleast one hydrophilic carrier. In specific embodiments, the hydrophiliccarrier is a hydrophilic triglyceride. In more specific embodiments, thehydrophilic triglyceride is a polyoxylated castor oil, or a polyoxylatedhydrogenated castor oil. In some embodiments, any pharmaceuticalcomposition provided herein consists essentially of a lipophilic carrieror combination of lipophilic carriers. In certain embodiments, anypharmaceutical composition provided herein comprises a lipophiliccarrier and less than 10% w/w or less than 5% w/w of a hydrophiliccarrier.

Provided in certain embodiments herein is a delayed release oral dosageform comprising (i) a therapeutically effective amount of one or moretestosterone C₂-C₁₃ alkyl ester; and (ii) at least one pharmaceuticallyacceptable carrier; wherein a single dose of the delayed release oraldosage form provides a mean plasma C_(max) of testosterone that is atleast 5% lower; or at least 10% lower than the mean plasma C_(max) oftestosterone that is provided by a single dose of an immediate releaseoral dosage form having an identical amount of the testosterone C₂-C₁₃alkyl ester. In some embodiments, the testosterone C₂-C₁₃ alkyl ester istestosterone undecanoate. In certain embodiments, the pharmaceuticalcomposition comprises about 10 mg to about 1000 mg of testosteroneC₂-C₁₃ alkyl ester.

In some embodiments, a single dose of any delayed release oral dosageform provided herein provides a mean plasma C_(max) of the that is atleast 5%, at least 10% or at least 15% lower than the mean plasmaC_(max) of testosterone C₂-C₁₃ alkyl ester that is provided by a singledose of an immediate release oral dosage form having an identical amountof the testosterone C₂-C₁₃ alkyl ester. In some embodiments, a singleadministration to a human of a dose of the delayed release oral dosageform provides a ratio of testosterone equivalent dose from the C₂-C₁₃alkyl ester present in the dose of the delayed release oral dosage formto mean plasma testosterone C_(max) provided by the singleadministration of the dose of the delayed oral release dosage form, theratio being about 500×10⁶ mL or less. In certain embodiments, a singledose of any delayed release oral dosage form provided herein provides amean plasma C_(max) of that is at least 5% lower than the mean plasmaC_(max) of dihydrotestosterone provided by a single dose of an immediaterelease oral dosage form having an identical amount of the testosteroneC₂-C₁₃ alkyl ester. In some embodiments, a single administration to ahuman a dose of the delayed release oral dosage form provides a ratio oftestosterone equivalent dose from the C₂-C₁₃ alkyl ester to mean plasmadihydroxytestosterone C_(max) provided by the single administration ofthe dose of the delayed oral release dosage form, the ratio being about350×10⁶ mL or less. In some embodiments, any delayed release oral dosageform provided herein provides a mean plasma C_(max) at steady state oftestosterone C₂-C₁₃ alkyl ester that is at least 5% lower, or at least10% lower than the mean plasma C_(max) of testosterone C₂-C₁₃ alkylester at steady state provided by an immediate release oral dosage formhaving an identical amount of the testosterone C₂-C₁₃ alkyl ester (e.g.,when orally administered to a testosterone deficient individual b.i.d.or q.d.).

In certain embodiments, any delayed release oral dosage form providedherein comprises at least one pharmaceutically acceptable carrier thatcomprises at least one hydrophilic carrier. In specific embodiments, thehydrophilic carrier is a hydrophilic triglyceride. In more specificembodiments, the hydrophilic triglyceride is a polyoxylated castor oil,or a polyoxylated hydrogenated castor oil. In some embodiments, anydelayed release oral dosage form provided herein consists essentially ofa lipophilic carrier or combination of lipophilic carriers. In someembodiments, a lipophilic carrier selected from the group consisting ofa monoglyceride, a diglyceride, a Vitamin E compound, a triglyceride, afatty acid, polyoxylated fatty acid, polyoxylated triglyceride,polyoxylated vegetable oil, and a combination thereof. In certainembodiments, any delayed release oral dosage form provided hereincomprises a lipophilic carrier and less than 10% w/w or less than 5% w/wof a hydrophilic carrier.

Provided in some embodiments herein is a pharmaceutical compositioncomprising (i) a therapeutically effective amount of one or moretestosterone alkyl ester; and (ii) at least one pharmaceuticallyacceptable carrier; the pharmaceutical composition releasing about 60%to about 90%, about 60% to about 85%, or about 60% to about 80% of thetestosterone alkyl ester after 1 hour in an aqueous medium. In certaininstances, the aqueous medium comprises 8% w/v octoxynol-9 in water atabout 37° C.

Provided in certain embodiments herein is a pharmaceutical compositioncomprising (i) a therapeutically effective amount of one or moretestosterone alkyl ester; and (ii) at least one pharmaceuticallyacceptable carrier; the pharmaceutical composition releasing about 50%or less, about 45% or less, or about 40% or less of the testosteronealkyl ester after 6 hour in an aqueous medium. In certain instances, theaqueous medium comprises 8% w/v octoxynol-9 in water at about 37° C.

Provided in some embodiments herein is a method of treating androgendeficiency in an individual in need thereof by administering to theindividual any pharmaceutical composition or dosage form describedherein. In a specific embodiment, provided herein is a method oftreating androgen deficiency in an individual in need thereof byadministering to the individual a pharmaceutical composition comprising(i) a therapeutically effective amount of one or more testosteroneC₂-C₁₃ alkyl ester; and (ii) at least one pharmaceutically acceptablecarrier. In specific embodiments, the pharmaceutical compositionreleases about 80% or less; or 90% or less of the testosterone C₂-C₁₃alkyl ester after 30 minutes in an aqueous medium. In some embodiments,the pharmaceutical composition releases about 50% or less of thetestosterone C₂-C₁₃ alkyl ester after 1 hour in an aqueous medium. Incertain embodiments, the pharmaceutical composition is administered witha meal. In some embodiments, the pharmaceutical composition isadministered b.i.d. or q.d. In various embodiments, a method providedherein has a release or pharmacokinetic profile as described herein. Insome embodiments, an oral testosterone undecanoate therapy describedherein provides to a human a ratio of a testosterone equivalent dosefrom the testosterone C₂-C₁₃ alkyl ester to mean steady statetestosterone C_(max), the ratio being about 500×10⁶ mL or less.

Also provided in some embodiments herein is an oral testosteroneundecanoate therapy that provides to a human in need of androgen therapyby orally delivering to the human a composition comprising atherapeutically effective amount of testosterone undecanoate. In someembodiments, the therapy provides to the human a mean C_(max) oftestosterone that is less than about 15 ng/mL, or less than about 19ng/mL after a single administration of the composition. In certainembodiments, the oral testosterone undecanoate therapy provides to thehuman a mean plasma C_(max) of dihydrotestosterone that is about 3.6ng/mL, or less; or about 4.5 ng/mL, or less after a singleadministration of the composition. In some embodiments, the oraltestosterone undecanoate therapy provides to the human a testosteronemean plasma C_(max) at steady state of about 1300 ng/dL or less after asingle administration of the composition. In certain embodiments, theoral testosterone undecanoate therapy provides to the human atestosterone mean plasma C_(min) at steady state of about 200 ng/dL ormore after a single administration of the composition. In someembodiments, the oral testosterone undecanoate therapy provides to thehuman a ratio of a testosterone equivalent dose to a mean stead statetestosterone C_(max) of about 500×10⁶ mL or less after a singleadministration of the composition. In certain embodiments, the oraltestosterone undecanoate therapy provides to the human a differencebetween a mean plasma C_(max) of testosterone at steady state and meanplasma C_(min) of testosterone at steady state of about 11 ng/mL orless; or about 16 ng/mL or less. In some embodiments, the oraltestosterone undecanoate therapy provides to the human a differencebetween a mean plasma C_(max) at steady state and mean plasma C_(min) atsteady state of testosterone alkyl ester of about 200 ng/mL or less.

Provided in certain embodiments herein is a pharmaceutical compositioncomprising (i) a therapeutically effective amount of one or moretestosterone alkyl ester; and (ii) a single (e.g., one and only one)lipid component solubilizing the testosterone alkyl ester. In someembodiments, provided herein is a pharmaceutical composition comprisinga therapeutically effective amount of testosterone undecanoate; thepharmaceutical composition providing an increase in testosterone alkylester in plasma compared to an otherwise identical pharmaceuticalcomposition comprising a testosterone alkyl ester other thantestosterone undecanoate. In certain embodiments, provided herein is apharmaceutical composition comprising (i) a therapeutically effectiveamount of one or more testosterone alkyl ester; and (ii) at least onepharmaceutically acceptable carrier; the pharmaceutical compositionproviding, when administered as a single dose to an individual, a doseof testosterone equivalent from the testosterone alkyl ester, to meansteady state AUC_(0−∞)ratio of about 500×10³ mL/h or less.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention may be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention, in certain embodiments, areutilized, and the accompanying drawings of which:

FIG. 1 illustrates the release profiles of Capsules 1-4 subjected to USPApparatus 2 at 37° C. and 100 rpm.

FIG. 2 illustrates the mean plasma testosterone concentrations followingadministration of several oral dosage forms described herein and animmediate release oral dosage.

FIG. 3 illustrates the mean plasma testosterone undecanoateconcentrations following administration of several oral dosage formsdescribed herein and an immediate release oral dosage.

FIG. 4 illustrates the mean plasma dihydrotestosterone concentrationsfollowing administration of several oral dosage forms described hereinand an immediate release oral dosage.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are pharmaceutical compositions and methods of using thesame. In some embodiments, the pharmaceutical compositions areformulated for oral delivery as an oral dosage form. In certainembodiments, a pharmaceutical composition described herein comprises asteroidal compound and at least one pharmaceutically acceptable carrier.In some embodiments, a pharmaceutical composition described herein is anoral dosage form comprising a steroidal compound and at least onepharmaceutically acceptable carrier. In specific embodiments, thesteroidal compound is a steroidal androgen (e.g., testosterone,dihydrotestosterone, analogs, or prodrugs thereof). In certainembodiments, analogs or prodrugs of testosterone include, e.g., estersof testosterone. In specific embodiments, the esters of testosteroneinclude, e.g., alkyl (e.g., straight chain, branched, cyclic,unsaturated, partially saturated, fully saturated and the like) estersof testosterone. Specifically, alkyl esters of testosterone include, byway of non-limiting example, lower alkyl esters (e.g., testosteroneC₂-C₁₃ alkyl esters such as testosterone propionate, testosteroneenanthate, or testosterone undecanoate), or higher alkyl esters (e.g.,testosterone C₁₄₊ alkyl esters such as testosterone palmitate). Infurther embodiments, the alkyl esters of testosterone include, by way ofnon-limiting example, cycloalkylalkyl esters (e.g., testosteronecypionate), cycloalkyl esters, and alkylcycloalkyl esters. In morespecific embodiments, the testosterone alkyl ester is testosteroneundecanoate. In certain embodiments, alkyl groups of the alkyl estersand/or other positions of the steroidal compound (e.g., testosteronealkyl ester, such as testosterone undecanoate) described herein areoptionally substituted, e.g., with one or more halogen, hydroxy group,amino group, or the like, or combinations thereof.

In various embodiments, the pharmaceutical compositions are formulatedfor androgen (e.g., testosterone) therapy. In certain instances, theandrogen therapy is an androgen (e.g., testosterone) replacementtherapy. In some embodiments, the androgen replacement therapy isutilized to treat individuals suffering from androgen deficiency (e.g.,postmenopausal women, menopausal women, sexually dysfunctional women,andropausal men, hypogonadal men, and the like) or treat individuals inneed of increased androgen levels. In some embodiments, the androgen(e.g., testosterone) replacement therapy is utilized for the treatmentof individuals diagnosed with or exhibiting symptoms of androgen (e.g.,testosterone) deficiency including, e.g., in aging men.

Provided in certain embodiments herein are pharmaceutical compositionsthat provide a plasma C_(max) of testosterone that is less than 1500ng/dL in at least 85% of a population of individuals (followingadministration of a single dose and/or in the steady state) whenadministered to a population of individuals (e.g., adult and/orpubescent human males). In some embodiments a pharmaceutical compositiondescribed herein provides a plasma C_(max) of testosterone that is lessthan 1800 ng/dL in at least 95% of a population of individuals(following administration of a single dose and/or in the steady state)when administered to a population of individuals (e.g., adult and/orpubescent human males). In some embodiments the oral dosage formsprovide a plasma C_(max) of testosterone that is less than 2500 ng/dL inall individuals (following administration of a single dose and/or in thesteady state) when administered to a population of individuals (e.g.,adult and/or pubescent human males). In some embodiments, theindividuals are adult humans. In specific embodiments, the adult humansare adult hypogonadal or otherwise androdeficient male humans.

In certain instances, normal human male testes produce four to eightmilligrams of testosterone daily and human females produce less. Withincertain contexts of the invention described herein, it will be generallyrecognized by those of skill in the art that the physiological “normal”range of total testosterone in men is about 250 to about 1,100 nanogramsper deciliter (ng/dL) and in healthy women is about 11 ng/dL to about 78ng/dL. Journal of Clinical Endocrinology & Metabolism, 85(7):2395-401.

Provided in some embodiments herein are pharmaceutical compositions thatprovide a C_(min) that is about 10 ng/dL or greater and a C_(max) thatis about 100 ng/dL or less in at least 50%, at least 60%, at least 70%,at least 80%, at least 90%, at least 95% of adult female humans (e.g.,postmenopausal or otherwise androdeficient female humans) whenadministered to a population of adult female humans (followingadministration of a single dose and/or in the steady state). Provided insome embodiments herein are pharmaceutical compositions that provide aC_(min) that is about 12 ng/dL or greater and a C_(max) that is about 82ng/dL or less in at least 50%, at least 60%, at least 70%, at least 80%,at least 90%, at least 95% of adult female humans (e.g., postmenopausalor otherwise androdeficient female humans) when administered to apopulation of adult female humans (following administration of a singledose and/or in the steady state).

In some embodiments, the pharmaceutical composition provided herein is adelayed release oral dosage form comprising a steroidal compound and atleast one pharmaceutically acceptable carrier. In certain instances, thedelayed release oral dosage forms release the active in an aqueousmedium (e.g., water, gastric fluid, or an aqueous solution with a pH ofabout 5.8) at a rate slower than an immediate or fast release oraldosage form (e.g., as measured by the amount of active found in theaqueous medium). In some embodiments, delayed release oral dosage formscomprise a steroidal compound, at least one hydrophilic carrier. Infurther embodiments, delayed release oral dosage forms comprise asteroidal compound, at least one hydrophilic carrier, and at least onelipidic and/or lipophilic carrier. In still further embodiments, thedelayed release oral dosage form comprises at least one steroidalcompound, at least one hydrophilic carrier, at least one lipidic and/orlipophilic carrier, and at least one viscosity enhancer or solidifyingagent. In still further embodiments, the delayed release oral dosageform comprises at least one steroidal compound and at least oneviscosity enhancer or solidifying agent. In some embodiments, apharmaceutical composition provided herein is formulated, e.g., with theviscosity enhancing agent or solidifying agent, to provide a solid, asemi-solid, a gel, a jelly, a paste, or the like. In specificembodiments, the delayed release oral dosage form is a capsule (e.g., ahard- or soft-gel capsule, a tablet or other solid dosage form). In someembodiments, the delayed release dosage form provided herein comprisesthe active (e.g., one or more testosterone alkyl ester such astestosterone undecanoate) in different release fractions (e.g., animmediate release portion and a delayed release portion). In specificembodiments, pharmaceutical compositions or dosage forms provided hereincomprise one or more of an immediate release portions or fractions, fastrelease portions or fractions, or combinations thereof and anenteric-release portion or fraction, sustained-release portion orfraction, controlled-release portion or fraction, extended-releaseportion or fraction, pulsatile-release portion or fraction,timed-release portion or fraction, or combinations thereof.

Pharmaceutical Compositions

In certain embodiments, provided herein is a pharmaceutical compositioncomprising at least one steroidal compound (e.g., testosterone,dihydrotestosterone, estradiol, or analogs or prodrugs thereof) and atleast one pharmaceutically acceptable carrier. In specific embodiments,the steroidal compound is a steroidal androgen (e.g., testosterone,dihydrotestosterone, or prodrugs thereof). In some embodiments, thesteroidal compound is an alkylated, hydroxy-alkylated and/orhydroxy-alkoylated natural steroid (e.g., testosterone alkyl ester,dihydrotestosterone alkyl ester, estradiol alkyl ester, or the like). Incertain embodiments, analogs or prodrugs of testosterone include, e.g.,esters of testosterone. In specific embodiments, the esters oftestosterone include, e.g., alkyl (e.g., straight chain, branched,cyclic, unsaturated, partially saturated, fully saturated and the like)esters of testosterone. Specifically, alkyl esters of testosteroneinclude, by way of non-limiting example, lower alkyl esters (e.g.,testosterone C₂-C₁₃ alkyl esters such as testosterone propionate,testosterone enanthate, or testosterone undecanoate), or higher alkylesters (e.g., testosterone C₁₄₊ alkyl esters such as testosteronepalmitate). In further embodiments, the alkyl esters of testosteroneinclude, by way of non-limiting example, cycloalkylalkyl esters (e.g.,testosterone cypionate), cycloalkyl esters, and alkylcycloalkyl esters.In more specific embodiments, the testosterone alkyl ester istestosterone undecanoate. In some embodiments, the at least onesteroidal compound comprises (1) a testosterone lower alkyl ester (e.g.,testosterone propionate, testosterone enanthate, or testosteroneundecanoate); and (2) a testosterone higher alkyl ester (e.g.,testosterone palmitate). Generally, as used herein, a pharmaceuticalcomposition comprising a steroidal compound includes the disclosure of apharmaceutical composition comprising one or more steroidal compounds.

In certain embodiments, any pharmaceutical composition described hereincomprises a therapeutically effective amount of at least one steroidalcompound (e.g., a testosterone alkyl ester, such as testosteroneundecanoate). In some embodiments, a therapeutically effective amount ofa steroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) is divided into one or more oral dosage form.In some embodiments, the one or more of the oral dosage forms describedherein collectively comprise a therapeutically effective amount of atestosterone alkyl ester (e.g., testosterone undecanoate). Thus, in someembodiments, the therapeutically effective amount of a steroidalcompound (e.g., a testosterone alkyl ester, such as testosteroneundecanoate) within a pharmaceutical composition described herein mayvary when the pharmaceutical composition is administered in combinationwith another therapy. Furthermore, therapeutically effective amounts ofa formulation may depend on the specific formulation within which the atleast one steroidal compound is found. For example, in some embodiments,more than one steroidal compound is present in a pharmaceuticalcomposition described herein. Thus, when there is a combination ofsteroidal compounds, in certain instances one or both of the steroidalcompounds present has a therapeutically effective amount that is lowerthan is required when the steroidal compounds are administeredseparately or alone. In some embodiments, a pharmaceutical compositiondescribed herein further comprises an adjuvant, which, in certaininstances, allows for a lower amount of a steroidal compound to beutilized as a therapeutically effective amount.

In certain embodiments, a pharmaceutical composition described hereincomprises about 1 mg to about 1.5 g, about 10 mg to about 1000 mg, orabout 10 mg to about 200 mg of a steroidal compound (e.g., atestosterone alkyl ester, such as testosterone undecanoate). In specificembodiments, a pharmaceutical composition described herein comprisesabout 10 mg to about 50 mg, about 15 mg to about 40 mg, about 20 mg, toabout 30 mg, or about 25 mg of steroidal compound (e.g., a testosteronealkyl ester, such as testosterone undecanoate). In other embodiments, apharmaceutical composition described herein comprises about 70 mg toabout 150 mg, about 80 mg to about 140 mg, about 90 mg to about 140 mg,about 100 mg to about 130 mg, about 110 mg to about 130 mg, or about 120mg of a steroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate). In some embodiments, a pharmaceuticalcomposition described herein comprises about 0.1 mg to about 5 mg of asteroidal compound (e.g., a testosterone alkyl ester such astestosterone undecanoate) per kg of an individual to whom the oraldosage form is to be administered. In certain embodiments, apharmaceutical composition described herein comprises an amount of asteroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) sufficient to provide about 1 mg to about 1 g,about 5 mg to about 500 mg, about 10 mg to about 300 mg, or about 20 toabout 250 mg of a steroidal compound (e.g., a testosterone alkyl ester,such as testosterone undecanoate) to an individual upon once a day,twice a day, three times a day, or four times a day oral administration.

In some embodiments, the at least one pharmaceutically acceptablecarrier is any carrier suitable for delivering an efficacious amount ofa steroidal compound, e.g., a testosterone alkyl ester, to anindividual. In some embodiments, the at least one pharmaceuticallyacceptable carrier is or comprises a hydrophilic carrier (e.g., ahydrophilic surfactant or hydrophilic additive). In certain embodiments,the at least one pharmaceutically acceptable carrier is a lipophiliccarrier (e.g., a lipophilic surfactant or lipophilic additive). In someembodiments, the at least one pharmaceutically acceptable carrier is ahydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilicadditive) and a lipophilic carrier (e.g., a lipophilic surfactant orlipophilic additive). In certain embodiments, the hydrophilic carrier isa hydrophilic triglyceride. In specific embodiments, the hydrophilictriglyceride is a polyoxylated castor oil, or a polyoxylatedhydrogenated castor oil. In some embodiments, any pharmaceuticalcomposition provided herein consists essentially of a lipophilic carrieror combination of lipophilic carriers. In certain embodiments, anypharmaceutical composition provided herein comprises a lipophiliccarrier and less than 10% w/w, less than 5% w/w or is substantially freeof a hydrophilic carrier. In certain embodiments, any pharmaceuticalcomposition provided herein comprises a lipophilic carrier and less than10% w/w, less than 5% w/w or is substantially free of a hydrophiliccarrier. In some embodiments, the pharmaceutical composition comprisinga carrier (e.g., a hydrophilic carrier and/or a lipophilic carrier), thepharmaceutical composition is a solid, a semi-solid, a gel, a jelly, apaste, or the like. In certain embodiments, e.g., wherein apharmaceutical composition comprising a hydrophilic carrier and/or alipophilic carrier, a viscosity enhancing agent or a solidifying agentis utilized to afford a pharmaceutical composition that is a solid, asemi-solid, a gel, a jelly, a paste, or the like. Thus, in certainembodiments, the at least one pharmaceutically acceptable carrier is ahydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilicadditive) and a viscosity enhancing or solidifying agent. In certainembodiments, the at least one pharmaceutically acceptable carrier is alipophilic carrier (e.g., a lipophilic surfactant or lipophilicadditive) and a viscosity enhancing or solidifying agent. In someembodiments, the at least one pharmaceutically acceptable carrier is orcomprises a hydrophilic carrier (e.g., a hydrophilic surfactant orhydrophilic additive), a lipophilic carrier (e.g., a lipophilicsurfactant or lipophilic additive), and a viscosity enhancing orsolidifying agent. In some embodiments, the at least onepharmaceutically acceptable carrier is or comprises an amphiphilic orzwitterionic carrier (e.g., an amphiphilic surfactant or amphiphilicadditive). In certain embodiments, the pharmaceutically acceptablecarrier is any carrier suitable for achieving one or more of thepharmacokinetic and/or pharmacodynamic profiles set forth herein.

Additives useful herein include chemical substances that are generallypharmacologically inactive. Further, the additive may be solid, liquidor semi-solid in nature at about ambient room temperature. Furthermore,the additive may be hydrophilic or lipophilic. In certain instances, a“hydrophilic additive” is a substance that has at least one polar sidegroup in its chemical structure which will attract water; whereas a“lipophilic additive” exhibits a tendency to repel water.

In some embodiments, the hydrophilic or lipophilic additive is containedwithin the components forming a composition and/or pharmaceutical dosageform thereof. In certain embodiments, the hydrophilic or lipophilicadditive is in an encapsulation coat in compositions. Alternatively, theadditives can be comprised in the pharmaceutical composition but not aspart of the composition itself. Specific, non-limiting examples ofadditives are described below.

Suitable additives include any additive that can facilitate theprocesses involving the preparation of a pharmaceutical compositionand/or dosage form described herein. In some instances, such additivesinclude those commonly utilized to facilitate the processes involvingthe preparation of a composition and/or a pharmaceutical dosage formdescribed herein. These processes include agglomeration, air suspensionchilling, air suspension drying, balling, coacervation, comminution,compression, pelletization, cryopelletization, encapsulation, extrusion,granulation, homogenization, inclusion complexation, lyophilization,nanoencapsulation, melting, mixing, molding, pan coating, solventdehydration, sonication, spheronization, spray chilling, spraycongealing, spray drying, or other processes known in the art. Incertain instances, the additive is optionally pre-coated orencapsulated. Suitable additives are optionally utilized to influencethe drug release from the composition and/or pharmaceutical dosage form.

Suitable additives utilized in various embodiments described hereininclude, by way of non-limiting example, adsorbing agents,anti-adherents, anticoagulants, antifoaming agents, antioxidants,anti-caking agents, anti-static agents, binders, bile acids, bufferants,bulking agents, chelating agents, coagulants, colorants, co-solvent,opaquants, congealing agents, coolants, cryoprotectants, diluents,dehumidifying agents, desiccants, desensitizers, disintegrants,dispersing agents, enzyme inhibitors, glidants, fillers, hydratingagent, super disintegrants, gums, mucilages, hydrogen bonding agents,enzymes, flavorants, humectants, humidifying agents, lubricant oils,ion-exchange resins, lubricants, plasticizers, pH modifying agents,preservatives, solidifying agent, solvents, solubilizers, spreadingagent sweeteners, stabilizers, surface area enhancing agents, suspendingagent, thickeners, viscosity increasing agents, waxes and mixturesthereof.

Some non-limiting examples of the hydrophilic or lipophilic additivessuitable for the current invention are as follows:

Alcohols and/or Polyols (e.g. ethanol, isopropanol, butanol, benzylalcohol, ethylene glycol, propylene glycol, glycerol, sorbitol,mannitol, dimethyl isosorbide, polyethylene glycol, fatty acid alcohol,vinyl alcohol polypropylene glycol, polyvinylalcohol, tocopherols,cellulose cyclodextrins, other derivatives, forms, mixtures thereof, orthe like); ethers of polyethylene glycols having an average molecularweight of about 200 to about 20,000 (e.g. tetrahydrofurfuryl alcohol PEGether, methoxy PEG, or the like); Amides (e.g. 2-pyrrolidone,2-piperidone, ε-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide, polyvinylpyrrolidone and the like.); Esters (e.g.ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyltributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethylbutyrate, triacetin, propylene glycol monoacetate, propylene glycoldiacetate, ε-caprolactone and isomers thereof, δ-valerolactone andisomers thereof, β-butyrolactone and isomers thereof; and otheradditives known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, or the like); Amino acids (e.g. P-aminobenzamidine,sodium glycocholate) mesylate; Amino acids and modified amino acids(e.g. aminoboronic acid derivatives and n-acetylcysteine; Peptides andmodified peptides (e.g. bacitracin, phosphinic acid dipeptidederivatives, pepstatin, antipain, leupeptin, chymostatin, elastin,bestatin, phoshporamindon, puromycin, cytochalasin potatocarboxypeptidase inhibitor, amastatin, or the like); Polypeptide proteaseinhibitors; Mucoadhesive polymers (e.g. polyacrylate derivatives,chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain,polyacrylic acid, carboxymethyl cellulose etc.); or the like; orcombinations thereof.

Some more examples of suitable additives for compositions and/or dosageforms described herein include, by way of non-limiting example, talc,magnesium stearate, silica (e.g. fumed silica, micronized silica,magnesium aluminum silicate etc.) and/or derivatives, polyethyleneglycols, surfactants, waxes, oils, cetyl alcohol, polyvinyl alcohol,stearic acid, stearic acid salts, stearic acid derivatives, starch,hydrogenated vegetable oils, hydrogenated castor oils, sodium benzoate,sodium acetate, leucine, PEG, alkyl sulfate salts; acetylatedmonoglycerides; long-chain alcohols; silicone derivatives; butylatedhydroxy toluene (BHT), butylated hydroxyl anisole (BHA), gallic acid,propyl gallate, ascorbic acid, ascorbyl palmitate,4-hydroxymethyl-2,6-di-tert-butyl phenol, dry starch, dry sugars,polyvinyl pyrrolidones, starch paste, methacrylic copolymers, bentonite,sucrose, polymericcellulose derivatives, shellac, sugar syrup; cornsyrup; polysaccharides, acacia, tragacanth, guar gum, xanthan gums;alginates; gelatin; gelatin hydrolysate; agar; sucrose; dextrose; PEG,vinyl pyrrolidone copolymers, poloxamers; pregelatinized starch,sorbitol, glucose); acetic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid,acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid and uric acid, vinegar,pharmaceutically acceptable bases, such as an amino acid, an amino acidester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodiumhydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesiumhydroxide, magnesium aluminum silicate, synthetic aluminum silicate,synthetic hydrotalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamin; salt of a pharmaceutically acceptablecation and an anion; EDTA and EDTA salts; titanium dioxide, food dyes,lakes, natural vegetable colorants, iron oxides, silicates, sulfates,magnesium hydroxide and aluminum hydroxide; halogenated hydrocarbons,trichloroethane, trichloroethylene, dichloromethane,fluorotrichloromethane, diethylether, trehelose, phosphates, citricacid, tartaric acid, gelatin, dextran and mannitol, lactose, mannitol,sodium chloride, potassium chloride, spray-dried lactose, hydrolyzedstarches, directly compressible starch, microcrystalline cellulose,cellulosic derivatives, sorbitol, sucrose, sucrose-based materials,calcium sulfate, dibasic calcium phosphate, dextrose, croscarmellosesodium, starch, starch derivatives, clays, gums, cellulose, cellulosederivates, alginates, crosslinked polyvinylpyrrolidone, sodium starchglycolate and microcrystalline cellulose, magnesium oxide, magnesiumcarbonates; desensitizers, spray-dried flavors, essential oils, ethylvanillin, styrene/divinyl benzene copolymers, quaternary ammoniumcompounds, polyethylene glycol, citrate esters (such as triethylcitrate, acetyl triethyl citrate, acetyltributyl citrate), acetylatedmonoglycerides, glycerin, triacetin, propylene glycol, phthalate esters(e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol anddibutyl sebacate, ascorbic acid, boric acid, sorbic acid, benzoic acid,and salts thereof, parabens, phenols, benzyl alcohol, and quaternaryammonium compounds; alcohols, ketones, esters, chlorinated hydrocarbonswater; sweeteners, (e.g. maltose, sucrose, glucose, sorbitol, glycerinand dextrins, aspartame, saccharine, saccharine salts, glycyrrhizin),viscosity modifiers, sugars, polyvinylpyrrolidone, cellulosics,polymers, gums and/or alginates.

Additives can also be materials such as proteins (e.g., collagen,gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates(e.g., alginates, carrageenan, cellulose derivatives, pectin, starch,chitosan); gums (e.g., xanthan gum, gum arabic); spermaceti; natural orsynthetic waxes; carnauba wax; fatty acids (e.g., stearic acid,hydroxystearic acid); fatty alcohols; sugars; shellacs, such as thosebased on sugars (e.g., lactose, sucrose, dextrose) or starches;polysaccharide-based shellacs (e.g., maltodextrin and maltodextrinderivatives, dextrates, cyclodextrin and cyclodextrin derivatives);cellulosic-based polymers (e.g., ethyl cellulose, methyl cellulose,microcrystalline cellulose, sodium carboxymethyl cellulose,hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose,HPMC acid succinates, cellulose acetate, cellulose nitrate, celluloseacetate butyrate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropylmethyl cellulose phthalate), shellacs;inorganics, such as dicalcium phosphate, hydroxyapitite, tricalciumphosphate, talc and titania; polyols, such as mannitol, xylitol andsorbitol; polyethylene glycol esters; and polymers, such as alginates,poly(lactide coglycolide), gelatin, crosslinked gelatin, and agar-agar.

It should be appreciated that there is considerable overlap between theabove-listed additives in common usage, since a given hydrophilic orlipophilic additive is often classified differently by differentpractitioners in the field, or is commonly used for any of severaldifferent or overlapping functions. Thus, the above-listed hydrophilicor lipophilic additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in compositionsof the present invention. In certain embodiments, the amounts of suchadditives are optionally adjusted and/or determined by one skilled inthe art, according to the particular properties desired.

In certain embodiments, the at least one pharmaceutically acceptablecarrier comprises at least one hydrophilic carrier (e.g., hydrophilicsurfactant). In some embodiments, the hydrophilic carrier is apolyoxylated glyceride (e.g., mono-, di-, or tri-glyceride), apolyoxylated vegetable oil, a polyoxylated hydrogenated vegetable oil, apolyoxylated fatty acid (mono-, or di-substituted), combinationsthereof, or the like. In certain embodiments, the at least onepharmaceutically acceptable carrier comprises or further comprises alipophilic carrier. Lipophilic carriers are selected from, by way ofnon-limiting example, a lipophilic surfactant, a vegetable oil (e.g.,castor oil), a fatty acid, a fatty alcohol, a glyceride (e.g., mono-,di-, or tri-glyceride), a hydrogenated vegetable oil, a Vitamin Ecompound (e.g., d,l-α-tocopherol), a triglyceride, a fatty acid,polyoxylated fatty acid, polyoxylated triglyceride, polyoxylatedvegetable oil, or combinations thereof. In some embodiments,polyoxylated compounds include polyethoxylated compounds.

In certain embodiments, the at least one hydrophilic carriers make upabout 1% to about 99% w/w, about 2% to about 80% w/w, about 2% to about50% w/w, or about 10% to about 40% w/w of any pharmaceutical compositiondescribed herein. In some embodiments, lipophilic carriers make up about1% w/w to about 99% w/w, about 2% to about 80% w/w, about 10% w/w toabout 80% w/w, about 30% w/w, to about 80% w/w, or about 40% to about80% w/w of any pharmaceutical composition described herein.

In specific embodiments, provided herein is a pharmaceutical composition(e.g., a delayed release dosage form) comprising a hydrophilic carrier.In more specific embodiments, the hydrophilic carrier is or comprises apolyoxylated vegetable oil (e.g., a polyoxylated, hydrogenated vegetableoil). In still more specific embodiments, a polyoxylated vegetable oilis a polyoxylated castor oil (e.g., a polyoxylated, hydrogenated castoroil). In certain embodiments, the lipidic and/or lipophilic carrier isnot a C₆-C₁₈ fatty acid. In some embodiments, the lipophilic carrier isa C₂₀₊ fatty acid. In some embodiments, the lipidic and/or lipophiliccarrier is not a fatty acid or an un-modified (e.g., non-polyoxylated)vegetable oil. In more specific embodiments, the lipidic and/orlipophilic carrier is not oleic acid or castor oil. In certain specificembodiments provided herein is a pharmaceutical composition (e.g., adelayed release dosage form) comprising an amphiphilic carrier. In morespecific embodiments, the amphiphilic carrier is or comprises azwitterionic choline (e.g., phosphatidylcholine). In some specificembodiments, provided herein is a pharmaceutical composition (e.g., adelayed release dosage form) comprising a lipophilic carrier. In morespecific embodiments, the lipophilic carrier is or comprises, by way ofnon-limiting example, a mono-, di- or triglyceride (e.g., glycerolmonolinoleate).

In some embodiments, the at least one pharmaceutically acceptablecarrier comprises at least one hydrophilic carrier, and at least onelipidic and/or lipophilic carrier. In further embodiments, the at leastone pharmaceutically acceptable carrier comprises at least onehydrophilic carrier, at least one lipidic and/or lipophilic carrier, andat least one viscosity enhancer or solidifying agent. In someembodiments, the solidifying agent is a polyethylene glycol (e.g., ahigh molecular weight polyethylene glycol, such as PEG 8000). Inspecific embodiments, a pharmaceutical composition described hereincomprises, along with a steroidal agent (e.g., a testosterone alkylester), a hydrogenated and polyoxylated castor oil and a polyethyleneglycol. In more specific embodiments, the pharmaceutical compositioncomprising a hydrogenated and polyoxylated castor oil and a polyethyleneglycol further comprises an additional lipidic and/or lipophiliccarrier. In some embodiments, the additional lipidic and/or lipophiliccarrier is a monoglyceride, a diglyceride, a Vitamin E compound, or acombination thereof.

In certain embodiments, pharmaceutical compositions described hereininclude oral dosage forms or delayed release oral dosage forms of any ofTables A to Q. In Tables A to Q, approximate weight percentages of thecompositions formulated into the capsules are provided. In specificembodiments, the steroidal compound of any of Capsules A1 to Q2comprises an alkyl ester testosterone (e.g., testosterone undecanoate).In certain instances, provided in the tables are non-limiting gradesand/or sources of components utilized. Disclosure provided in Tables Ato Q is not limited to the grades and/or sources described.

TABLE A Capsule A1 Capsule A2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 1-50 10-30 Hydrophilic Carrier 1-90 10-30 LipophilicCarrier 1-90 40-70 Solidifying Agent (additive) 1-20  5-10

TABLE B Capsule B1 Capsule B2 Component % w/w % w/w Testosteroneundecanoate (~10-1000 mg) 1-50 15 Polyoxyl 40 Hydrogenated Castor Oil,NF 1-50 16 Glycerol Monolinoleate, NF (Maisine 35-1) 30-90  63Polyethylene Glycol 8000, USP 1-20 6

TABLE C Capsule C1 Component % w/w Capsule C2 Testosterone undecanoate(~10-1000 mg) 1-50 25 Polyoxyl 35 Castor Oil, NF 1-50 21 Vitamin E, USP(d,l-α-tocopherol) 30-90  48 Polyethylene Glycol 8000, USP 1-20 6

TABLE D Capsule D1 Capsule D2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-30 Lauryl macrogol glyceride (Gelucire 51 20-9044/14) Stearoyl macrogol glyceride (Gelucire 34 10-90 50/13)

TABLE E Capsule E1 Capsule E2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 20 10-30 C8-C18 macrogol glyceride (Gelucire 35 10-7043/01) Polyglyceryl-3-oleate (Caprol 3GO) 45  5-60

TABLE F Capsule F1 Capsule F2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-25  Lauryl macrogol glyceride (Gelucire 40 5-8044/14) Vitamin E 30 2-60 Hypromellose (Methocel K100 M LV, 15 5-25 CR)

TABLE G Capsule G1 Capsule G2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-30  PEG-40 hydrogenated Castor Oil 60 5-80(Cremophor ® RH40) Polyethylene glycol 8000 15 5-40 Hypromellose(Methocel K100 M LV, 10 5-25 CR)

TABLE H Capsule H1 Capsule H2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-30  Corn Glycerides (Maisine 35-1) 60 5-90Polyethylene glycol 8000 20 5-70

TABLE I Capsule I1 Capsule I2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 25 10-30  PEG-40 hydrogenated Castor Oil 15 5-80(Cremophor ® RH40) Vitamin E 20 2-60 Corn Glycerides (Maisine 35-1) 305-50 Polyethylene Glycol 8000 10 5-20

TABLE J Capsule J1 Capsule J2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-30  Hydrogenated vegetable oil 50 2-80 Polyethyleneglycol 8000 35 2-80

TABLE K Capsule K1 Capsule K2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 50 30-60 Corn Glycerides (Maisine 35-1) 50 30-60

TABLE L Capsule L1 Capsule L2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 40 30-60 Fish Oil 50 30-60 Vitamin E 10  3-15

TABLE M Capsule M1 Capsule M2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 40 30-60 Omega-3-acid esters 50 30-60 Polyethylene glycol8000 5  3-15

TABLE N Capsule N1 Capsule N2 Component % w/w % w/w Testosteroneundecanoate 5-30 10-20 Polyoxyl 40 Hydrogenated Castor Oil, NF 5-3010-20 Glyceryl Monolinoleate, NF (Maisine 50-90  55-70 35-1)Polyethylene Glycol 8000, USP 1-15 3-8

TABLE O Capsule O1 Capsule O2 Component % w/w % w/w Testosteroneundecanoate 10-40 20-30 Polyoxyl 35 Castor Oil, NF 10-30 15-25 VitaminE, USP (d,l-α-tocopherol) 30-70 40-55 Polyethylene Glycol 8000, USP 1-15 3-8

Polyethylene Glycol 8000, USP 1-15 3-8

TABLE P Capsule P1 Capsule P2 Component % w/w % w/w Testosteroneundecanoate 10-40 20-25 Vitamin E Polyethylene Glycol 10-40 20-25Succinate, NF Vitamin E, USP (d,l-tocopherol) 15-60 30-40 PolyethyleneGlycol 8000, USP  1-10 2-6 Hypromellose (100 cP, K100  5-40 15-25Premium LV)

TABLE Q Capsule Q1 Capsule Q2 Component % w/w % w/w Testosteroneundecanoate 10-40 20-25 Vitamin E Polyethylene Glycol 10-40 20-25Succinate, NF Vitamin E, USP (d,l-tocopherol) 15-60 30-40 PolyethyleneGlycol 8000, USP  1-10 2-6 Hypromellose (4,000 cP, K4M)  5-40 15-25

In certain embodiments, any pharmaceutical composition described herein,e.g., a pharmaceutical composition of any of Tables A to Q can beprepared by (i) combining and heating all ingredients until a moltenmixture is obtained (e.g., 50-70° C.); and (ii) encapsulating an amountof molten mixture comprising a select dose (e.g., a therapeuticallyeffective amount or a partial dose of a therapeutically effectiveamount) of steroidal compound to obtain an oral dosage form. In certaininstances, the molten mixture is spray-congealed to obtain beads. Insome instances, the molten mixture is sprayed onto inert cores (e.g.,sugar spheres) to obtain coated cores. In certain embodiments, suchbeads, cores, or similar forms are encapsulated or otherwise formulatedto provide an oral dosage form. In some instances, the molten mixture isadmixed, uniformly dispersed, or granulated over a carrier andcompressed into a tablet dosage form. In certain embodiments, prior tocompression, the molten mixture/carrier composition is further mixedwith one or more pharmaceutical aid including, by way of non-limitingexample, glidants, lubricants, binders, or the like. In someembodiments, the carrier is a therapeutically inert carrier such as, byway of non-limiting example, microcrystalline cellulose, starch,lactose, or the like.

In some embodiments, compositions described herein (e.g., compositionsset forth in Tables K to M), are optionally filled into a delayedrelease capsule or shell, or are otherwise coated or encapsulated with adelayed release coat.

Pharmacokinetics and Pharmacodynamics

Provided in certain embodiments herein are androgen therapies (e.g.,testosterone undecanoate therapies), pharmaceutical compositions andoral dosage forms that provide a plasma C_(max) of testosterone that isless than 1500 ng/dL in at least 85% of a population of individuals(following administration of a single dose and/or in the steady state)when administered to a population of individuals. In some embodimentsthe androgen therapies (e.g., testosterone undecanoate therapies),pharmaceutical compositions or oral dosage forms provide a plasmaC_(max) of testosterone that is less than 1800 ng/dL in at least 95% ofa population of individuals (following administration of a single doseand/or in the steady state) when administered to a population ofindividuals (e.g., adult and/or pubescent human males). In someembodiments the androgen therapies (e.g., testosterone undecanoatetherapies), pharmaceutical compositions or oral dosage forms provide aplasma C_(max) of testosterone that is less than 2500 ng/dL in all orsubstantially all individuals (following administration of a single doseand/or in the steady state) when administered to a population ofindividuals (e.g., adult and/or pubescent human males). In someembodiments, the androgen therapies (e.g., testosterone undecanoatetherapies), pharmaceutical compositions and oral dosage forms provides aplasma C_(max) of testosterone that is less than 1500 ng/dL in at least85% and less than 1800 ng/dL in at least 95% of a population ofindividuals (following administration of a single dose and/or in thesteady state) when administered to a population of individuals (e.g.,adult and/or pubescent human males). In certain embodiments, theandrogen therapies (e.g., testosterone undecanoate therapies),pharmaceutical compositions and oral dosage forms provides a plasmaC_(max) of testosterone that is less than 1500 ng/dL in at least 85%,less than 1800 ng/dL in at least 95%, and less than 2500 ng/dL in atleast 99% of a population of individuals (following administration of asingle dose and/or in the steady state) when administered to apopulation of individuals (e.g., adult and/or pubescent human males). Insome embodiments, the androgen therapies (e.g., testosterone undecanoatetherapies), pharmaceutical compositions and oral dosage forms provides aplasma C_(max) of testosterone that is less than 1500 ng/dL in at least85%, and less than 2500 ng/dL in at least 99% of a population ofindividuals (following administration of a single dose and/or in thesteady state) when administered to a population of individuals (e.g.,adult and/or pubescent human males). In some embodiments, the androgentherapies (e.g., testosterone undecanoate therapies), pharmaceuticalcompositions and oral dosage forms provides a plasma C_(max) oftestosterone that is less than 1800 ng/dL in at least 95%, and less than2500 ng/dL in at least 99% of a population of individuals (followingadministration of a single dose and/or in the steady state) whenadministered to a population of individuals (e.g., adult and/orpubescent human males). In some embodiments, as used in any descriptionherein, individuals are adult humans. In specific embodiments, the adulthumans are adult male humans. In certain embodiments, the individualsare adult hypogonadal adult male humans. Plasma concentrations describedherein are optionally obtained by administering a composition describedherein to human males, e.g., hypogonadal human males. In otherinstances, plasma concentrations are optionally obtained byadministering the composition to testosterone deficient human subjects(e.g., postmenopausal women) who provide a population representative ofthe effects of testosterone therapy on individuals with low levels oftestosterone. Clin. Endocrinology 2007, 66(4):570-85.

Provided in some embodiments herein are pharmaceutical compositions thatprovide a C_(min) that is about 10 ng/dL or greater and a C_(max) thatis about 100 ng/dL or less in at least 50%, at least 60%, at least 70%,at least 80%, at least 90%, at least 95% of adult female humans (e.g.,postmenopausal or otherwise androdeficient female humans) whenadministered to a population of adult female humans (followingadministration of a single dose and/or in the steady state). Provided insome embodiments herein are pharmaceutical compositions that provide aC_(min) that is about 12 ng/dL or greater and a C_(max) that is about 82ng/dL or less in at least 50%, at least 60%, at least 70%, at least 80%,at least 90%, at least 95% of adult female humans (e.g., postmenopausalor otherwise androdeficient female humans) when administered to apopulation of adult female humans (following administration of a singledose and/or in the steady state). In some embodiments, the adult femalehumans are sexually dysfunctional adult female humans. In certainembodiments, the adult female humans are postmenopausal female humans.

Pharmaceutical compositions and oral dosage forms described herein areformulated, in various embodiments, to achieve the pharmacokinetic andpharmacodynamic profiles herein in any suitable manner. In certaininstances, the desired pharmacokinetic and/or pharmacodynamic profiledescribed herein are obtained via the modification of dosage form, theat least one pharmaceutically acceptable carrier, the amount ofsteroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) present, combinations thereof, or the like. Incertain embodiments, the population of individuals is one, one or more,two or more, or a statistically significant number of individuals.

Provided in certain embodiments herein are androgen therapies (e.g.,testosterone undecanoate therapies), pharmaceutical compositions or oraldosage forms described herein that provide or are formulated to providea plasma concentration of testosterone at steady state that is betweenabout 200 ng/dL and 1300 ng/dL in at least 75%, at least 80%, at least85%, at least 90%, at least 95%, or at least 99% of a population ofindividuals when administered to the population of individuals. In someembodiments androgen therapies (e.g., testosterone undecanoatetherapies), pharmaceutical compositions or oral dosage forms describedherein provide or are formulated to provide a plasma concentration oftestosterone at steady state that is between about 200 ng/dL and 1100ng/dL in at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, or at least 99% of a population of individuals whenadministered to the population of individuals. In certain embodimentspharmaceutical compositions or oral dosage forms described hereinprovide or are formulated to provide a plasma concentration oftestosterone at steady state that is between about 300 ng/dL and 1000ng/dL in at least 50%, at least 60%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, or at least 99% ofa population of individuals when administered to the population ofindividuals.

In some embodiments, a pharmaceutical composition or oral dosage formdescribed herein (e.g., for use in a steroidal, such as testosteroneundecanoate, therapy) is formulated such that a single administration ofthe pharmaceutical composition or oral dosage form provides a meanplasma C_(max) of testosterone that is about 19 ng/mL or less, about 18ng/mL or less, about 17 ng/mL or less, about 16 ng/mL or less, about 15ng/mL or less, about 14 ng/mL or less, about 5 ng/mL to about 19 ng/mL,about 5 ng/mL to about 18 ng/mL, about 5 ng/mL to about 17 ng/mL, about5 ng/mL to about 16 ng/mL, about 5 ng/mL to about 15 ng/mL, about 5ng/mL to about 14 ng/mL, about 7 ng/mL to about 19 ng/mL, about 7 ng/mLto about 18 ng/mL, about 7 ng/mL to about 17 ng/mL, about 7 ng/mL toabout 16 ng/mL, about 7 ng/mL to about 15 ng/mL, about 7 ng/mL to about14 ng/mL, about 10 ng/mL to about 19 ng/mL, about 10 ng/mL to about 18ng/mL, about 10 ng/mL to about 17 ng/mL, about 10 ng/mL to about 16ng/mL, about 10 ng/mL to about 15 ng/mL, or about 10 ng/mL to about 14ng/mL. In specific embodiments, an oral dosage form described herein isformulated such that a single administration of the oral dosage formprovides a mean plasma C_(max) of testosterone that is about 15 ng/mL orless, about 19 ng/mL or less, about 5 ng/mL to about 19 ng/mL, or about5 ng/mL to about 15 ng/mL. In certain embodiments, a pharmaceuticalcomposition or oral dosage form described herein is formulated such thata single administration of the pharmaceutical composition or oral dosageform provides a mean plasma C_(max) of dihydrotestosterone that is about4.5 ng/mL or less, about 4.3 ng/mL or less, about 4.2 ng/mL or less,about 4.1 ng/mL or less, about 4 ng/mL or less, about 3.9 ng/mL or less,about 3.8 ng/mL or less, about 3.7 ng/mL or less, about 3.6 ng/mL orless, about 3.5 ng/mL or less, about 1.5 ng/mL to about 4.5 ng/mL, about1.5 ng/mL to about 3.9 ng/mL, about 1.5 ng/mL to about 3.8 ng/mL, about1.5 ng/mL to about 3.7 ng/mL, about 1.5 ng/mL to about 3.6 ng/mL, about1.5 ng/mL to about 3.5 ng/mL, about 2.0 ng/mL to about 4.5 ng/mL, about2.0 ng/mL to about 3.9 ng/mL, about 2.0 ng/mL to about 3.8 ng/mL, about2.0 ng/mL to about 3.7 ng/mL, about 2.0 ng/mL to about 3.6 ng/mL, about2.0 ng/mL to about 3.5 ng/mL, about 2.5 ng/mL to about 3.9 ng/mL, about2.5 ng/mL to about 3.8 ng/mL, about 2.5 ng/mL to about 3.7 ng/mL, about2.5 ng/mL to about 3.6 ng/mL, or about 2.5 ng/mL to about 3.5 ng/mL. Inspecific embodiments, a pharmaceutical composition or oral dosage formdescribed herein is formulated such that a single administration of thepharmaceutical composition or oral dosage form provides a mean plasmaC_(max) of dihydrotestosterone that is about 3.6 ng/mL or less upon oraladministration. In certain embodiments, a pharmaceutical composition ororal dosage form described herein is formulated such that a singleadministration of the pharmaceutical composition or oral dosage formprovides a mean plasma C_(max) of testosterone alkyl ester (e.g.,testosterone undecanoate) that is about 400 ng/mL or less, about 380ng/mL or less, about 360 ng/mL or less, about 340 ng/mL or less, about320 ng/mL or less, about 300 ng/mL or less, or about 280 ng/mL or less,about 100 ng/mL to about 400 ng/mL, about 100 ng/mL to about 380 ng/mL,about 100 ng/mL to about 360 ng/mL, about 100 ng/mL to about 340 ng/mL,about 100 ng/mL to about 320 ng/mL, about 100 ng/mL to about 300 ng/mL,about 100 ng/mL to about 280 ng/mL, about 150 ng/mL to about 400 ng/mL,about 150 ng/mL to about 380 ng/mL, about 150 ng/mL to about 360 ng/mL,about 150 ng/mL to about 340 ng/mL, about 150 ng/mL to about 320 ng/mL,about 150 ng/mL to about 300 ng/mL, about 150 ng/mL to about 280 ng/mL,about 200 ng/mL to about 400 ng/mL, about 200 ng/mL to about 380 ng/mL,about 200 ng/mL to about 360 ng/mL, about 200 ng/mL to about 340 ng/mL,about 200 ng/mL to about 320 ng/mL, about 200 ng/mL to about 300 ng/mL,or about 200 ng/mL to about 280 ng/mL. In specific embodiments, apharmaceutical composition or oral dosage form described herein isformulated such that a single administration of the pharmaceuticalcomposition or oral dosage form provides a mean plasma C_(max) oftestosterone undecanoate that is about 380 ng/mL or less upon oraladministration. In some embodiments, a pharmaceutical composition ororal dosage form described herein (e.g., for use in a steroidal, such astestosterone undecanoate, therapy) is formulated such that a singleadministration of the pharmaceutical composition or oral dosage formprovides a mean plasma C_(max) of testosterone that is about 5 ng/mL toabout 15 ng/mL, a mean plasma C_(max) of dihydrotestosterone that isabout 1.5 ng/mL to about 3.8 ng/mL, and a mean plasma C_(max) oftestosterone alkyl ester (e.g., testosterone undecanoate) that is about100 ng/mL to about 380 ng/mL. In certain embodiments, a pharmaceuticalcomposition or oral dosage form described herein (e.g., for use in asteroidal, such as testosterone undecanoate, therapy) is formulated suchthat a single administration of the pharmaceutical composition or oraldosage form provides a mean plasma C_(max) of testosterone that is about5 ng/mL to about 19 ng/mL, a mean plasma C_(max) of dihydrotestosteronethat is about 1.5 ng/mL to about 4.5 ng/mL, and a mean plasma C_(max) oftestosterone alkyl ester (e.g., testosterone undecanoate) that is about100 ng/mL to about 380 ng/mL.

In some embodiments, provided herein is a pharmaceutical composition ororal dosage form formulated such that it provides a mean plasmaconcentration of testosterone that is about 200 ng/dL or less, about 150ng/dL or less, about 100 ng/dL or less, or about 75 ng/dL or less, about5 ng/dL to about 200 ng/dL, about 5 ng/dL to about 150 ng/dL, about 5ng/dL to about 100 ng/dL, about 5 ng/dL to about 75 ng/dL, about 10ng/dL to about 200 ng/dL, about 10 ng/dL to about 150 ng/dL, about 10ng/dL to about 100 ng/dL, about 10 ng/dL to about 75 ng/dL, about 15ng/dL to about 200 ng/dL, about 15 ng/dL to about 150 ng/dL, about 15ng/dL to about 100 ng/dL, or about 15 ng/dL to about 75 ng/dL 1 hourafter a single oral administration. In certain embodiments, providedherein is a pharmaceutical composition or oral dosage form formulatedsuch that it provides a mean plasma concentration of testosterone thatis about 500 ng/dL or less, about 400 ng/dL or less, about 300 ng/dL orless, about 200 ng/dL or less, about 150 ng/dL or less, about 5 ng/dL toabout 500 ng/dL, about 5 ng/dL to about 400 ng/dL, about 5 ng/dL toabout 300 ng/dL, about 5 ng/dL to about 200 ng/dL, about 5 ng/dL toabout 150 ng/dL, about 10 ng/dL to about 500 ng/dL, about 10 ng/dL toabout 400 ng/dL, about 10 ng/dL to about 300 ng/dL, about 10 ng/dL toabout 200 ng/dL, about 10 ng/dL to about 150 ng/dL, about 15 ng/dL toabout 500 ng/dL, about 15 ng/dL to about 400 ng/dL, about 15 ng/dL toabout 300 ng/dL, about 15 ng/dL to about 200 ng/dL, about 15 ng/dL toabout 150 ng/dL 2 hour after a single oral administration. In someembodiments, provided herein is a pharmaceutical composition or oraldosage form formulated such that it provides a mean plasma concentrationof testosterone that is about 5 ng/dL to about 150 ng/dL 1 hour after asingle oral administration, and about 10 ng/dL to about 500 ng/dL 2hours after a single oral administration.

In certain embodiments, pharmaceutical compositions described hereincomprise or are formulated into one or more oral dosage form describedherein. Therefore, in some embodiments, in order to arrive at thetargeted plasma concentration (e.g., at a specific concentration at agiven time, C_(max), C_(min), or the like), a plurality of oral dosageforms described herein are optionally administered. Furthermore, as usedherein, a mean plasma concentration (e.g., at a specific concentrationat a given time, C_(max), C_(min), or the like) is the mean of aplurality of concentration values obtained from the plasma of aplurality of individuals following oral administration of an oral dosageform described herein to the plurality of individuals. In someembodiments, the individuals are adult humans. In specific embodiments,the adult humans are adult male humans. In certain embodiments, theindividuals are adult hypogonadal or otherwise androdeficient adult malehumans. In some embodiments, the individuals are postmenopausal orotherwise androdeficient adult female humans. Furthermore, it is notedthat concentrations of testosterone alkyl ester described herein includethe concentration of the one or more testosterone alkyl esteradministered.

In some embodiments, provided herein is a pharmaceutical composition ororal dosage form that releases or is formulated to release about 90% orless, about 80% or less, about 70% or less, about 60% or less, about 55%or less, about 50% or less, about 45% or less, about 40% or less, about35% or less, about 5% to about 90%, about 5% to about 80%, about 5% toabout 70%, about 5% to about 60%, about 5% to about 55%, about 5% toabout 50%, about 5% to about 45%, about 5% to about 40%, about 5% toabout 35%, about 20% to about 90%, about 20% to about 80%, about 20% toabout 70%, about 20% to about 60%, about 20% to about 55%, about 20% toabout 50%, about 20% to about 45%, about 20% to about 40%, or about 20%to about 35% of the testosterone alkyl ester (e.g., testosteroneundecanoate) after 1 hour in an aqueous medium (e.g., in 1 L deionizedwater comprising 8% w/v Triton X-100). In certain embodiments, providedherein is a pharmaceutical composition or oral dosage form that releasesor is formulated to release about 90% or less, about 80% or less, about70% or less, about 60% or less, about 50% or less, about 40% or less,about 30% or less, about 20% or less, about 2% to about 90%, about 2% toabout 80%, about 2% to about 70%, about 2% to about 60%, about 2% toabout 50%, about 2% to about 40%, about 2% to about 30%, about 2% toabout 20%, about 10% to about 90%, about 10% to about 80%, about 10% toabout 70%, about 10% to about 60%, about 10% to about 50%, about 10% toabout 40%, about 10% to about 30%, or about 10% to about 20% of thetestosterone alkyl ester (e.g., testosterone undecanoate) after 30minutes in an aqueous medium (e.g., in 1 L deionized water comprising 8%w/v Triton X-100). In some embodiments, provided herein is apharmaceutical composition or oral dosage form that releases or isformulated to release about 99% or less, about 98% or less, about 97% orless, about 96% or less, about 95% or less, about 90% or less, about 10%to about 99%, about 10% to about 98%, about 10% to about 97%, about 10%to about 96%, about 10% to about 95%, about 10% to about 90%, about 40%to about 99%, about 40% to about 98%, about 40% to about 97%, about 40%to about 96%, about 40% to about 95%, about 40% to about 90%, about 70%to about 99%, about 70% to about 98%, about 70% to about 97%, about 70%to about 96%, about 70% to about 95%, or about 70% to about 90% of thetestosterone alkyl ester (e.g., testosterone undecanoate) after 3 hourin an aqueous medium (e.g., in 1 L deionized water comprising 8% w/vTriton X-100). In some embodiments, provided herein is a pharmaceuticalcomposition or oral dosage form that releases or is formulated torelease more than 80% of the testosterone alkyl ester (e.g.,testosterone undecanoate) within 12, 10, 8, 6, 5, 4, 3, or 2 hours in anaqueous medium (e.g., in 1 L deionized water comprising 8% w/v TritonX-100). In specific embodiments, provided herein is a pharmaceuticalcomposition or oral dosage form that releases or is formulated torelease about 20% or less of the testosterone alkyl ester after 30minutes, 50% or less of the testosterone alkyl ester (e.g., testosteroneundecanoate) after 1 hour and about 95% or less of the testosteronealkyl ester after 3 hours in an aqueous medium (e.g., in 1 L deionizedwater comprising 8% w/v Triton X-100). In some embodiments, providedherein is a pharmaceutical composition or oral dosage form that releasesor is formulated to release about 5% to about 60% of the testosteronealkyl ester (e.g., testosterone undecanoate) after 1 hour, about 2% toabout 40% of the testosterone alkyl ester after 30 minutes, and about10% to about 95% of the testosterone alkyl ester after 2 hours in anaqueous medium (e.g., in 1 L deionized water comprising 8% w/v TritonX-100). In certain specific embodiments, provided herein is apharmaceutical composition or oral dosage form that releases or isformulated to release about 50% or less of the testosterone alkyl ester(e.g., testosterone undecanoate) after 1 hour, and 80% or less of thetestosterone alkyl ester (e.g., testosterone undecanoate) within 2-12hours (or after 12 hours, 10 hours, 8 hours, 6 hours, 5 hours, 4 hours,3 hours, or 2 hours) in an aqueous medium (e.g., in 1 L deionized watercomprising 8% w/v Triton X-100). In certain instances, the aqueousmedium is 1 L deionized water comprising 8% w/v Triton X-100 (e.g.,octylphenol ethylene oxide condensate; octoxynol-9;t-octylphenoxypolyethoxyethanol; t-oct-C₆H₄—(OCH₂CH₂)_(x)OH, x=9-10; CASNo. 9002-93-1; Triton X-100 was a registered trademark formerly owned byRohm and Haas Co., but now owned by Union Carbide) at 37±0.5° C. and thepharmaceutical composition or oral dosage form is deposited therein andsubjected to a paddle method at 100 rpm and 37±0.5° C. for thedesignated period of time (USP App 2).

In some embodiments, provided herein is a pharmaceutical composition ororal dosage form that provides or is formulated to provide atestosterone (e.g., in human males, adult human males, pubescent humanmales, or the like) mean plasma C_(max) at steady state of about 1550ng/dL or less, about 1500 ng/dL or less, about 1450 ng/dL or less, about1400 ng/dL or less, about 1310 ng/dL or less, about 1300 ng/dL or less.In some embodiments, provided herein is a pharmaceutical composition ororal dosage form that provides or is formulated to provide atestosterone (e.g., in human males, adult human males, pubescent humanmales, or the like) mean plasma C_(min) at steady state of about 100ng/dL or more, about 150 ng/dL or more, about 200 ng/dL or more, about250 ng/dL or more, or about 300 ng/dL or more. In specific embodiments,provided herein is a pharmaceutical composition or oral dosage form thatprovides or is formulated to provide a testosterone (e.g., in humanmales, adult human males, pubescent human males, or the like) meanplasma C_(min) at steady state of about 200 ng/dL or more. In certainembodiments, provided herein is a pharmaceutical composition or oraldosage form that provides or is formulated to provide a testosterone(e.g., in human males, adult human males, pubescent human males, or thelike) mean plasma concentration that ranges at steady state from about100 ng/dL to about 1500 ng/dL, about 150 ng/dL to about 1400 ng/dL,about 200 ng/dL to about 1300 ng/dL or about 250 ng/dL to about 1200ng/dL. In specific embodiments, provided herein is a pharmaceuticalcomposition or oral dosage form that provides or is formulated toprovide a testosterone (e.g., in human males, adult human males,pubescent human males, or the like) mean plasma concentration thatranges at steady state from about 200 ng/dL to about 1300 ng/dL.

In some embodiments, provided herein is a pharmaceutical composition ororal dosage form that provides or is formulated to provide atestosterone (e.g., in human females, adult human females, postmenopausal human females, or the like) mean plasma C_(max) at steadystate of about 110 ng/dL or less, 100 ng/dL or less, about 95 ng/dL orless, about 90 ng/dL or less, about 85 ng/dL or less, or about 82 ng/dLor less. In some embodiments, provided herein is a pharmaceuticalcomposition or oral dosage form that provides or is formulated toprovide a testosterone (e.g., in human females, adult human females,post menopausal human females, or the like) mean plasma C_(min) atsteady state of about 3 ng/dL or more, about 5 ng/dL or more, about 8ng/dL or more, about 10 ng/dL or more, or about 12 ng/dL or more. Inspecific embodiments, provided herein is a pharmaceutical composition ororal dosage form that provides or is formulated to provide atestosterone (e.g., in human females, adult human females, postmenopausal human females, or the like) mean plasma C_(min) at steadystate of about 8 ng/dL or more. In certain embodiments, provided hereinis a pharmaceutical composition or oral dosage form that provides or isformulated to provide a testosterone (e.g., in human males, adult humanfemales, pubescent human females, postmenopausal human females, or thelike) mean plasma concentration that ranges at steady state from about 5ng/dL to about 110 ng/dL, about 8 ng/dL to about 100 ng/dL, about 10ng/dL to about 90 ng/dL or about 12 ng/dL to about 82 ng/dL. In specificembodiments, provided herein is a pharmaceutical composition or oraldosage form that provides or is formulated to provide a testosterone(e.g., in human females, adult human females, post menopausal humanfemales, or the like) mean plasma concentration that ranges at steadystate from about 10 ng/dL to about 90 ng/dL.

Provided in certain embodiments herein is a pharmaceutical compositionor oral dosage form that provides or is formulated to provide upon oraladministration to an individual (e.g., an androgen deficient human male)a testosterone equivalent (e.g., mass of testosterone that can bederived from a testosterone alkyl ester (e.g., C₂-C₁₃)) dose to meansteady state testosterone C_(max) ratio of about 500×10⁶ mL or less. Insome embodiments, a testosterone equivalent dose to mean steady statetestosterone C_(max) ratio is about 500×10⁶ mL, or less; about 4×10⁵ mL,or more; about 6×10⁵ mL, or more; about 8×10⁵ mL, or more; about 1×10⁶mL, or more; about 3×10⁶ mL, or more; about 4×10⁶ mL, or more; about5×10⁶ mL, or more; about 6×10⁶ mL, or more; 500×10⁶ mL, or less; 400×10⁶mL, or less; 300×10⁶ mL, or less; 250×10⁶ mL, or less; 200×10⁶ mL, orless; 150×10⁶ mL, or less; 100×10⁶ mL, or less; about 25×10⁵ mL, ormore; about 100×10⁵ mL, or more; about 250×10⁵ mL, or more; about500×10⁵ mL, or more; about 4×10⁵ mL to about 500×10⁶ mL; about 4×10⁵ mLto about 400×10⁶ mL; about 4×10⁵ mL to about 300×10⁶ mL; about 4×10⁵ mLto about 250×10⁶ mL; about 4×10⁵ mL to about 200×10⁶ mL; about 4×10⁵ mLto about 150×10⁶ mL; about 20×10⁵ mL to about 500×10⁶ mL; about 20×10⁵mL to about 400×10⁶ mL; about 20×10⁵ mL to about 300×10⁶ mL; about20×10⁵ mL to about 250×10⁶ mL; about 20×10⁵ mL to about 200×10⁶ mL;about 20×10⁵ mL to about 150×10⁶ mL; about 50×10⁵ mL to about 500×10⁶mL; about 50×10⁵ mL to about 400×10⁶ mL; about 50×10⁵ mL to about300×10⁶ mL; about 50×10⁵ mL to about 250×10⁶ mL; about 50×10⁵ mL toabout 200×10⁶ mL; about 50×10⁵ mL to about 150×10⁶ mL; about 200×10⁵ mLto about 500×10⁶ mL; about 200×10⁵ mL to about 400×10⁶ mL; about 200×10⁵mL to about 300×10⁶ mL; about 200×10⁵ mL to about 250×10⁶ mL; about200×10⁵ mL to about 200×10⁶ mL; about 200×10⁵ mL to about 150×10⁶ mL; orthe like. In some embodiments, a single dose of any oral dosage form orpharmaceutical composition described herein provides, upon oraladministration to an individual (e.g., an androgen deficient humanmale), a ratio testosterone equivalent dose to mean plasma testosteroneC_(max) that is about 500×10⁶ mL or less. In some embodiments, a singleadministration provides a testosterone equivalent dose to meantestosterone C_(max) ratio that is about 500×10⁶ mL, or less; about4×10⁵ mL, or more; 500×10⁶ mL, or less; 400×10⁶ mL, or less; 300×10⁶ mL,or less; 250×10⁶ mL, or less; 200×10⁶ mL, or less; 150×10⁶ mL, or less;100×10⁶ mL, or less; about 25×10⁵ mL, or more; about 100×10⁵ mL, ormore; about 250×10⁵ mL, or more; about 500×10⁵ mL, or more; about 4×10⁵mL to about 500×10⁶ mL; about 4×10⁵ mL to about 400×10⁶ mL; about 4×10⁵mL to about 300×10⁶ mL; about 4×10⁵ mL to about 250×10⁶ mL; about 4×10⁵mL to about 200×10⁶ mL; about 4×10⁵ mL to about 150×10⁶ mL; about 20×10⁵mL to about 500×10⁶ mL; about 20×10⁵ mL to about 400×10⁶ mL; about20×10⁵ mL to about 300×10⁶ mL; about 20×10⁵ mL to about 250×10⁶ mL;about 20×10⁵ mL to about 200×10⁶ mL; about 20×10⁵ mL to about 150×10⁶mL; about 50×10⁵ mL to about 500×10⁶ mL; about 50×10⁵ mL to about400×10⁶ mL; about 50×10⁵ mL to about 300×10⁶ mL; about 50×10⁵ mL toabout 250×10⁶ mL; about 50×10⁵ mL to about 200×10⁶ mL; about 50×10⁵ mLto about 150×10⁶ mL; about 200×10⁵ mL to about 500×10⁶ mL; about 200×10⁵mL to about 400×10⁶ mL; about 200×10⁵ mL to about 300×10⁶ mL; about200×10⁵ mL to about 250×10⁶ mL; about 200×10⁵ mL to about 200×10⁶ mL;about 200×10⁵ mL to about 150×10⁶ mL; or the like. In some embodiments,a single administration provides a testosterone equivalent dose to meandihydroxytestosterone C_(max) ratio that is about 350×10⁶ mL, or less;about 20×10⁵ mL, or more; 500×10⁶ mL, or less; 400×10⁶ mL, or less;300×10⁶ mL, or less; 250×10⁶ mL, or less; 200×10⁶ mL, or less; 150×10⁶mL, or less; 100×10⁶ mL, or less; about 25×10⁵ mL, or more; about100×10⁵ mL, or more; about 250×10⁵ mL, or more; about 500×10⁵ mL, ormore; about 20×10⁵ mL to about 500×10⁶ mL; about 20×10⁵ mL to about400×10⁶ mL; about 20×10⁵ mL to about 300×10⁶ mL; about 20×10⁵ mL toabout 250×10⁶ mL; about 20×10⁵ mL to about 200×10⁶ mL; about 20×10⁵ mLto about 150×10⁶ mL; about 50×10⁵ mL to about 500×10⁶ mL; about 50×10⁵mL to about 400×10⁶ mL; about 50×10⁵ mL to about 300×10⁶ mL; about50×10⁵ mL to about 250×10⁶ mL; about 50×10⁵ mL to about 200×10⁶ mL;about 50×10⁵ mL to about 150×10⁶ mL; about 200×10⁵ mL to about 500×10⁶mL; about 200×10⁵ mL to about 400×10⁶ mL; about 200×10⁵ mL to about300×10⁶ mL; about 200×10⁵ mL to about 250×10⁶ mL; about 200×10⁵ mL toabout 200×10⁶ mL; about 200×10⁵ mL to about 150×10⁶ mL; or the like. Incertain instances, a steroid equivalent dose (e.g., testosteroneequivalent dose) of a composition or dosage form described herein is theamount of steroid compound (e.g., testosterone) present (e.g., thesteroidal portion of a steroidal compound, such as a testosterone alkylester) in the composition or dosage form and can be determined bycalculating, e.g., (mass testosterone/mass testosterone alkylester)*amount of testosterone alkyl ester in the composition or dosageform.

Provided in certain embodiments herein is a pharmaceutical compositionor oral dosage form that provides or is formulated to provide adifference between the mean plasma C_(max) of testosterone at steadystate and mean plasma C_(min) of testosterone at steady state that isabout 20 ng/mL or less, about 19 ng/mL or less, about 18 ng/mL or less,about 17 ng/mL or less, about 16 ng/mL or less, about 15 ng/mL or less,about 14 ng/mL or less, about 13 ng/mL or less, about 12 ng/mL or less,about 11 ng/mL or less, about 10.8 ng/mL or less, about 2 to about 20ng/mL, about 2 to about 18 ng/mL, about 2 to about 16 ng/mL, about 2 toabout 15 ng/mL, about 2 to about 14 ng/mL, about 2 to about 13 ng/mL,about 2 to about 12 ng/mL, about 2 to about 11 ng/mL, about 5 to about15 ng/mL, about 5 to about 14 ng/mL, about 5 to about 13 ng/mL, about 5to about 12 ng/mL, or about 5 to about 11 ng/mL. In specificembodiments, the pharmaceutical composition or oral dosage form providesor is formulated to provide a difference between the mean plasma C_(max)of testosterone at steady state and mean plasma C_(min) of testosteroneat steady state that is about 11 ng/mL or less. Furthermore, in someembodiments, provided herein is a pharmaceutical composition or oraldosage form provided herein provides or is formulated to provide adifference between the mean plasma C_(max) and the mean C_(min) oftestosterone alkyl ester (e.g., testosterone undecanoate) is about 275ng/mL or less, about 260 ng/mL or less, about 250 ng/mL or less, about240 ng/mL or less, about 230 ng/mL or less, about 225 ng/mL or less,about 220 ng/mL or less, about 210 ng/mL or less, about 200 ng/mL orless, about 190 ng/mL or less, or about 180 ng/mL or less. In specificembodiments, provided herein is a pharmaceutical composition or oraldosage form provided herein provides or is formulated to provide adifference between the mean plasma C_(max) and mean plasma C_(min) oftestosterone alkyl ester (e.g., testosterone undecanoate) is about 200ng/mL or less. In specific embodiments, provided herein is apharmaceutical composition or oral dosage form provided herein providesor is formulated to provide a difference between the mean plasma C_(max)and mean plasma C_(min) of testosterone alkyl ester (e.g., testosteroneundecanoate) is about 275 ng/mL or less.

In some embodiments, provided herein is a pharmaceutical composition ororal dosage form that is formulated such that it provides, following asingle oral administration, a mean plasma AUC_(0−∞) concentration oftestosterone of about 120 ng·h/mL or less, about 110 ng·h/mL or less,about 100 ng·h/mL or less, about 90 ng·h/mL or less, about 80 ng·h/mL orless, about 70 ng·h/mL or less, about 60 ng·h/mL or less, about 20ng·h/mL to about 110 ng·h/mL, about 20 ng·h/mL to about 100 ng·h/mL,about 20 ng·h/mL to about 90 ng·h/mL, about 20 ng·h/mL to about 80ng·h/mL, about 20 ng·h/mL to about 70 ng·h/mL, about 20 ng·h/mL to about60 ng·h/mL, about 30 ng·h/mL to about 110 ng·h/mL, about 30 ng·h/mL toabout 100 ng·h/mL, about 30 ng·h/mL to about 90 ng·h/mL, about 30ng·h/mL to about 80 ng·h/mL, about 30 ng·h/mL to about 70 ng·h/mL, about30 ng·h/mL to about 60 ng·h/mL, about 40 ng·h/mL to about 110 ng·h/mL,about 40 ng·h/mL to about 100 ng·h/mL, about 40 ng·h/mL to about 90ng·h/mL, about 40 ng·h/mL to about 80 ng·h/mL, about 40 ng·h/mL to about70 ng·h/mL, about 40 ng·h/mL to about 60 ng·h/mL, about 50 ng·h/mL toabout 110 ng·h/mL, about 50 ng·h/mL to about 100 ng·h/mL, about 50ng·h/mL to about 90 ng·h/mL, about 50 ng·h/mL to about 80 ng·h/mL, about50 ng·h/mL to about 70 ng·h/mL, about 60 ng·h/mL to about 110 ng·h/mL,about 60 ng·h/mL to about 100 ng·h/mL, about 60 ng·h/mL to about 90ng·h/mL, or about 60 ng·h/mL to about 80 ng·h/mL. In certainembodiments, provided herein is a pharmaceutical composition or oraldosage form that is formulated such that, following a single oraladministration, it provides a mean plasma AUC_(0∞) concentration ofdihydrotestosterone of about 50 ng·h/mL or less, about 45 ng·h/mL orless, about 40 ng·h/mL or less, about 35 ng·h/mL or less, about 30ng·h/mL or less, about 25 ng·h/mL or less, about 20 ng·h/mL or less,about 10 ng·h/mL to about 50 ng·h/mL, about 10 ng·h/mL to about 45ng·h/mL, about 10 ng·h/mL to about 40 ng·h/mL, about 10 ng·h/mL to about35 ng·h/mL, about 10 ng·h/mL to about 30 ng·h/mL, about 10 ng·h/mL toabout 25 ng·h/mL, about 10 ng·h/mL to about 20 ng·h/mL, about 15 ng·h/mLto about 50 ng·h/mL, about 15 ng·h/mL to about 45 ng·h/mL, about 15ng·h/mL to about 40 ng·h/mL, about 15 ng·h/mL to about 35 ng·h/mL, about15 ng·h/mL to about 30 ng·h/mL, about 15 ng·h/mL to about 25 ng·h/mL,about 20 ng·h/mL to about 50 ng·h/mL, about 20 ng·h/mL to about 45ng·h/mL, about 20 ng·h/mL to about 40 ng·h/mL, about 20 ng·h/mL to about35 ng·h/mL, or about 20 ng·h/mL to about 30 ng·h/mL. In someembodiments, provided herein is a pharmaceutical composition or oraldosage form that is formulated such that, following a single oraladministration, it provides a mean plasma AUC_(0−∞) concentration oftestosterone alkyl ester (e.g., the one or more testosterone alkyl estercompounds, such as testosterone undecanoate, found in the composition ordosage form) of about 1200 ng·h/mL or less, about 1100 ng·h/mL or less,about 1000 ng·h/mL or less, about 900 ng·h/mL or less, about 850 ng·h/mLor less, about 800 ng·h/mL or less, about 750 ng·h/mL or less, about 100ng·h/mL to about 1200 ng·h/mL, about 100 ng·h/mL to about 1100 ng·h/mL,about 100 ng·h/mL to about 1000 ng·h/mL, about 100 ng·h/mL to about 900ng·h/mL, about 100 ng·h/mL to about 850 ng·h/mL, about 100 ng·h/mL toabout 800 ng·h/mL, about 100 ng·h/mL to about 750 ng·h/mL, about 150ng·h/mL to about 1200 ng·h/mL, about 150 ng·h/mL to about 1100 ng·h/mL,about 150 ng·h/mL to about 1000 ng·h/mL, about 150 ng·h/mL to about 900ng·h/mL, about 150 ng·h/mL to about 850 ng·h/mL, about 150 ng·h/mL toabout 800 ng·h/mL, about 150 ng·h/mL to about 750 ng·h/mL, about 200ng·h/mL to about 1200 ng·h/mL, about 200 ng·h/mL to about 1100 ng·h/mL,about 200 ng·h/mL to about 1000 ng·h/mL, about 200 ng·h/mL to about 900ng·h/mL, about 200 ng·h/mL to about 850 ng·h/mL, about 200 ng·h/mL toabout 800 ng·h/mL, about 200 ng·h/mL to about 750 ng·h/mL, about 250ng·h/mL to about 1200 ng·h/mL, about 250 ng·h/mL to about 1100 ng·h/mL,about 250 ng·h/mL to about 1000 ng·h/mL, about 250 ng·h/mL to about 900ng·h/mL, about 250 ng·h/mL to about 850 ng·h/mL, about 250 ng·h/mL toabout 800 ng·h/mL, about 250 ng·h/mL to about 750 ng·h/mL, about 300ng·h/mL to about 1200 ng·h/mL, about 300 ng·h/mL to about 1100 ng·h/mL,about 300 ng·h/mL to about 1000 ng·h/mL, about 300 ng·h/mL to about 900ng·h/mL, about 300 ng·h/mL to about 850 ng·h/mL, about 300 ng·h/mL toabout 800 ng·h/mL, or about 300 ng·h/mL to about 750 ng·h/mL.

Provided in certain embodiments herein is any oral dosage form orpharmaceutical composition described herein that when a single dose isadministered to an individual provides a testosterone equivalent dose tomean testosterone AUC_(0−∞) ratio of about 500×10³ mL/h or less. In someembodiments, the testosterone equivalent dose to mean AUC_(0−∞) ratio isabout 20×10³ mL/h, or more; about 30×10³ mL/h, or more; about 40×10³mL/h, or more; about 50×10³ mL/h, or more; about 60×10³ mL/h, or more;about 80×10³ mL/h, or more; about 100×10³ mL/h, or more; about 600×10³mL/h, or less; about 400×10³ mL/h, or less; about 350×10³ mL/h, or less;about 250×10³ mL/h, or less; about 200×10³ mL/h, or less; about 150×10³mL/h, or less; about 10 to about 600×10³ mL/h; about 20 to about 500×10³mL/h; about 30 to about 450×10³ mL/h; about 20 to about 400×10³ mL/h;about 50 to about 300×10³ mL/h; about 50 to about 200×10³ mL/h; or thelike.

In certain embodiments, a pharmaceutical composition or oral dosage formdescribed herein achieves steady state upon administration in any mannersuitable to achieve the steady state, e.g., once a day, twice a day,three times a day, four times a day, or the like. In specificembodiments, steady state is achieved after a period of time of b.i.d.oral administration (e.g., every 12 hours) of an oral dosage formdescribed herein. In certain embodiments, steady state is obtainedafter, e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks orlonger, if or as necessary. In specific embodiments, steady state isobtained after b.i.d. oral administration for 5-7 days. Moreover, steadystate plasma concentrations of testosterone, testosterone alkyl ester(e.g., testosterone undecanoate), and dihydrotestosterone are obtained,in certain instances, by administration of pharmaceutical compositionscomprising about 1 mg to about 1 g, or about 10 mg to about 200 mg of asteroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate). In specific embodiments, a pharmaceuticalcomposition (e.g., for administration to a human male) comprises about10 mg to about 50 mg, about 15 mg to about 40 mg, about 20 mg, to about30 mg, or about 25 mg of steroidal compound (e.g., a testosterone alkylester, such as testosterone undecanoate). In other embodiments, apharmaceutical composition (e.g., for administration to a human male)comprises about 70 mg to about 150 mg, about 80 mg to about 140 mg,about 90 mg to about 140 mg, about 100 mg to about 130 mg, about 110 mgto about 130 mg, about 80 mg, or about 120 mg of a steroidal compound(e.g., a testosterone alkyl ester, such as testosterone undecanoate). Insome embodiments, steady state of a testosterone, testosterone alkylester (e.g., testosterone undecanoate), and dihydrotestosterone areobtained by the administration of about 0.1 mg to about 5 mg of asteroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) per kg of an individual to whom the oraldosage form is to be administered. In certain embodiments, testosterone,testosterone alkyl ester (e.g., testosterone undecanoate), anddihydrotestosterone are obtained by the oral administration of about 1mg to about 1 g, about 5 mg to about 500 mg, about 10 mg to about 300mg, or about 20 to about 250 mg of a steroidal compound (e.g., atestosterone alkyl ester, such as testosterone undecanoate) to anindividual upon once a day, twice a day, three times a day, or fourtimes a day. In certain embodiments, the pharmacokinetic and/orpharmacodynamic profiles described herein are obtained as a function ofdose of steroidal compound and/or formulation of the pharmaceuticalcomposition. In certain embodiments, an oral dosage form foradministration to a human female comprises about 10% as much of atestosterone alkyl ester as does an oral dosage form for administrationto a human male. In some embodiments, a pharmaceutical composition fordelivery to an adult human female comprises about 5 mg to about 50 mg,about 5 mg to about 30 mg, about 7 mg to about 15 mg, about 8 mg toabout 14 mg, about 9 mg to about 14 mg, about 10 mg to about 13 mg,about 11 mg to about 13 mg, about 8 mg, or about 12 mg of a testosteronealkyl ester, such as testosterone undecanoate.

Provided in certain embodiments herein is a pharmaceutical compositionor oral dosage form that provides or is formulated to provide a delayedrelease dosage form. In specific embodiments, any delayed release oraldosage form described herein comprises one or more steroidal compound(e.g., one or more testosterone alkyl ester, such as testosteroneundecanoate). In certain embodiments, a delayed release dosage form isone that releases about 90% or less, about 80% or less, about 70% orless, about 60% or less, about 55% or less, about 50% or less, about 45%or less, about 40% or less, about 35% or less, about 5% to about 90%,about 5% to about 80%, about 5% to about 70%, about 5% to about 60%,about 5% to about 55%, about 5% to about 50%, about 5% to about 45%,about 5% to about 40%, about 5% to about 35%, about 20% to about 90%,about 20% to about 80%, about 20% to about 70%, about 20% to about 60%,about 20% to about 55%, about 20% to about 50%, about 20% to about 45%,about 20% to about 40%, or about 20% to about 35% of the steroidalcompound (e.g., a testosterone alkyl ester, such as testosteroneundecanoate) after 1 hour in an aqueous medium; releases about 90% orless, about 80% or less, about 70% or less, about 60% or less, about 50%or less, about 40% or less, about 30% or less, about 20% or less, about2% to about 90%, about 2% to about 80%, about 2% to about 70%, about 2%to about 60%, about 2% to about 50%, about 2% to about 40%, about 2% toabout 30%, about 2% to about 20%, about 10% to about 90%, about 10% toabout 80%, about 10% to about 70%, about 10% to about 60%, about 10% toabout 50%, about 10% to about 40%, about 10% to about 30%, or about 10%to about 20% of the steroidal compound (e.g., a testosterone alkylester, such as testosterone undecanoate) after 30 minutes in an aqueousmedium; releases about 99% or less, about 98% or less, about 97% orless, about 96% or less, about 95% or less, about 90% or less, about 10%to about 99%, about 10% to about 98%, about 10% to about 97%, about 10%to about 96%, about 10% to about 95%, about 10% to about 90%, about 40%to about 99%, about 40% to about 98%, about 40% to about 97%, about 40%to about 96%, about 40% to about 95%, about 40% to about 90%, about 70%to about 99%, about 70% to about 98%, about 70% to about 97%, about 70%to about 96%, about 70% to about 95%, or about 70% to about 90% of thesteroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) after 3 hour in an aqueous medium; and/orreleases more than 80% of the steroidal compound (e.g., a testosteronealkyl ester, such as testosterone undecanoate) contained therein within12, 10, 8, 6, 5, 4, 3, or 2 hours in an aqueous medium. Conversely, insome embodiments an immediate release dosage form (e.g., a fast releasedosage form) comprising a steroidal compound (e.g., a testosterone alkylester, such as testosterone undecanoate) releases about 90% or more ofthe steroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) contained therein within about 15 minutes ofexposure to an aqueous medium. In some instances, the aqueous medium ispresent in a USP Type-II (paddle) apparatus with conditions at 37±0.5°C. and at 100 rpm. In more specific instances, the aqueous medium isabout 1 L of DI water having 8% w/v of Triton X-100. Furthermore, insome embodiments, an immediate release dosage form of steroidal compound(e.g., a testosterone alkyl ester, such as testosterone undecanoate) isan oral dosage form (e.g., capsule) comprising the steroidal compound(e.g., a testosterone alkyl ester, such as testosterone undecanoate)formulated in a mixture of castor oil and propylene glycol laurate(e.g., a composition comprising testosterone undecanoate, castor oil andpropylene glycol laurate, as currently marketed under the tradenameANDRIOL); or the steroidal compound (e.g., a testosterone alkyl ester,such as testosterone undecanoate) formulated in oleic acid (e.g., acomposition comprising testosterone undecanoate and oleic acid, aspreviously marketed under the tradename ANDRIOL).

Furthermore, provided herein is a delayed release oral dosage formformulated such that it provides, following a single oraladministration, a mean plasma concentration of testosterone that is atleast 50% lower, at least 40% lower, at least 30% lower, at least 20%lower, at least 10% lower, at least 5% lower, about 50-95% lower, about40-95% lower, about 30-95% lower, about 20-95% lower, about 50-90%lower, about 40-80% lower, about 30-80% lower, about 20-80% lower, about40-60% lower, or about 10-95% lower measured after about 1 hour than isprovided by a single dose of an immediate release oral dosage formhaving the same amount of steroidal compound (e.g., a testosterone alkylester, such as testosterone undecanoate). In specific embodiments,provided herein is a delayed release oral dosage form formulated suchthat it provides, following a single oral administration, a mean plasmaconcentration of testosterone that is at least 20% lower measured afterabout 1 hour than is provided by a single dose of an immediate releaseoral dosage form. In some embodiments, provided herein is a delayedrelease oral dosage form formulated such that it provides, following asingle oral administration, a mean plasma concentration of testosteronethat is at least 50% lower, at least 40% lower, at least 30% lower, atleast 20% lower, at least 10% lower, about 50-95% lower, about 40-95%lower, about 30-95% lower, about 20-95% lower, about 40-60% lower, about20-80% lower, about 10-60% lower, or about 10-95% lower measured afterabout 2 hours than is provided by a single dose of an immediate releaseoral dosage form. In specific embodiments, provided herein is a delayedrelease oral dosage form formulated such that it provides, following asingle oral administration, a mean plasma concentration of testosteronethat is at least 20% lower measured after about 2 hours than is providedby a single dose of an immediate release oral dosage form. In certainembodiments, provided herein is a delayed release oral dosage formformulated such that it provides, following a single oraladministration, a mean plasma concentration of testosterone that is atleast 50% lower, at least 40% lower, at least 30% lower, at least 20%lower, at least 10% lower, about 50-95% lower, about 40-95% lower, about30-95% lower, about 20-95% lower, about 50-80% lower, about 40-80%lower, about 30-60% lower, about 20-50% lower, about 10-50% lower, orabout 10-95% lower measured after about 3 hours than is provided by asingle dose of an immediate release oral dosage form. In specificembodiments, provided herein is a delayed release oral dosage formformulated such that it provides, following a single oraladministration, a mean plasma concentration of testosterone that is atleast 20% lower measured after about 3 hours than is provided by asingle dose of an immediate release oral dosage form.

Provided in some embodiments herein is a delayed release oral dosageform formulated such that it provides, following a single oraladministration, a mean plasma C_(max) of testosterone that is at least25% lower, at least 20% lower, at least 15% lower, at least 10% lower,at least 5% lower, about 25-95% lower, about 20-99% lower, about 15-99%lower, about 10-99% lower, about 25-50% lower, about 20-60% lower, about15-40% lower, about 10-60% lower, about 5-30%lower, or about 5-99% lowerthan the mean plasma C_(max) of testosterone that is provided by asingle dose of an immediate release oral dosage form having an identicalamount of the steroidal compound (e.g., a testosterone alkyl ester, suchas testosterone undecanoate) as is present in the delayed release oraldosage form. In certain embodiments, provided herein is a delayedrelease oral dosage form that provides or is formulated to provide,following a single oral administration, a mean plasma C_(max) of thetestosterone alkyl ester (e.g., testosterone undecanoate) that is atleast 25% lower, at least 20% lower, at least 15% lower, at least 10%lower, at least 5% lower, about 25-95% lower, about 20-99% lower, about15-99% lower, about 10-99% lower, about 5-99% lower, about 25-90% lower,about 20-80% lower, about 15-60% lower, about 10-60% lower, or about5-40% lower than the mean plasma C_(max) of testosterone alkyl esterthat is provided by a single dose of an immediate release oral dosageform having an identical amount of the steroidal compound (e.g., atestosterone alkyl ester, such as testosterone undecanoate) as ispresent in the delayed release oral dosage form. In some embodiments,provided herein is a delayed release oral dosage form that provides oris formulated to provide, following oral administration, a mean plasmaC_(max) of dihydrotestosterone that is at least 10% lower, at least 8%lower, at least 7% lower, at least 6% lower, at least 5% lower, about10-95% lower, about 8-99% lower, about 7-99% lower, about 6-99% lower,about 5-99% lower, about 5-15% lower, about 10-90% lower, about 8-80%lower, about 7-60% lower, about 10-60% lower, or about 5-40% lower thanthe mean plasma C_(max) of dihydrotestosterone provided by a single doseof an immediate release oral dosage form having an identical amount ofthe steroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) as is present in the delayed release oraldosage form.

Provided in certain embodiments herein is a delayed release oral dosageform that provides or is formulated to provide a mean plasma C_(max) atsteady state of testosterone alkyl ester that is at least 20% lower, atleast 15% lower, at least 10% lower, at least 5% lower, about 20-95%lower, about 15-99% lower, about 10-99% lower, about 20-99% lower, about15-99% lower, about 10-99% lower, about 5-99% lower, about 20-90% lower,about 20-80% lower, about 15-60% lower, about 10-60% lower, or about5-40% lower than the mean plasma C_(max) of steroidal compound (e.g., atestosterone alkyl ester, such as testosterone undecanoate) at steadystate provided by an immediate release oral dosage form having anidentical amount of the testosterone alkyl ester as is present in thedelayed release oral dosage form. In some embodiments, a delayed oraldosage form comprising testosterone alkyl ester provided herein providesor is formulated to provide a mean plasma C_(max) at steady state oftestosterone that is at least 20% lower, at least 15% lower, at least10% lower, at least 5% lower, about 20-95% lower, about 15-99% lower,about 10-99% lower, about 20-99% lower, about 15-99% lower, about 10-99%lower, about 10-30% lower, about 20-90% lower, about 20-80% lower, about15-60% lower, about 10-60% lower, or about 10-40% lower than the meanplasma C_(max) of testosterone at steady state provided by an immediaterelease oral dosage form having an identical amount of the steroidalcompound (e.g., a testosterone alkyl ester, such as testosteroneundecanoate) as is present in the delayed release oral dosage form.

In some embodiments, the delayed release oral dosage form provides afluctuation index of testosterone at steady state that is at least 20%lower, at least 15% lower, at least 10% lower, at least 5% lower, about20-95% lower, about 15-99% lower, about 10-99% lower, about 20-99%lower, about 15-99% lower, about 10-99% lower, about 5-99% lower, about20-90% lower, about 20-80% lower, about 15-60% lower, about 10-60%lower, or about 5-40% lower than a fluctuation index of testosterone atsteady state of an immediate release oral dosage form having anidentical amount of the steroidal compound (e.g., a testosterone alkylester, such as testosterone undecanoate) as is present in the delayedrelease oral dosage form. In certain embodiments, the delayed releaseoral dosage form provides a fluctuation index of testosterone alkylester at steady state that is at least 20% lower, at least 15% lower, atleast 10% lower, at least 5% lower, about 20-95% lower, about 15-99%lower, about 10-99% lower, about 20-99% lower, about 15-99% lower, about10-99% lower, about 5-99% lower, about 20-90% lower, about 20-80% lower,about 15-60% lower, about 10-60% lower, or about 5-40% lower than afluctuation index of testosterone alkyl ester at steady state of animmediate release oral dosage form having an identical amount of thetestosterone alkyl ester as is present in the delayed release oraldosage form. In some embodiments, a pharmaceutical composition or oraldosage form provided herein that does not comprise oleate provides afluctuation index of testosterone at steady state that is at least 20%lower, at least 15% lower, at least 10% lower, at least 5%, about 20-95%lower, about 15-99% lower, about 10-99% lower, about 20-99% lower, about15-99% lower, about 10-99% lower, about 5-99% lower, about 20-90% lower,about 20-80% lower, about 15-60% lower, about 10-60% lower, or about5-40% lower than a fluctuation index of testosterone at steady stateprovided by an oleate-containing oral dosage form having an identicalamount of the steroidal compound (e.g., a testosterone alkyl ester, suchas testosterone undecanoate). In certain embodiments, a pharmaceuticalcomposition or oral dosage form provided herein that does not containcastor oil (unmodified by polyoxylation or hydrogenation) provides afluctuation index of testosterone alkyl ester at steady state that is atleast 20% lower, at least 15% lower, at least 10% lower, at least 5%lower, about 20-95% lower, about 15-99% lower, about 10-99% lower, about20-99% lower, about 15-99% lower, about 10-99% lower, about 5-99% lower,about 20-90% lower, about 20-80% lower, about 15-60% lower, about 10-60%lower, or about 5-40% lower than a fluctuation index of testosteronealkyl ester at steady state of an castor oil-containing oral dosage formhaving an identical amount of the steroidal compound (e.g., atestosterone alkyl ester, such as testosterone undecanoate). As utilizedherein, the fluctuation index is the difference between the mean plasmaC_(max) and mean plasma C_(min) values that are achieved afteradministration of a dosage form.

In some embodiments, provided herein is a delayed oral dosage form thatis formulated such that it provides, following a single oraladministration, a mean plasma AUC_(0−∞) concentration of testosterone ofthat is at least 40%, at least 50% or at least 60% of the mean plasmaAUC_(0−∞) concentration of testosterone provided by an immediate releasedosage form.

Methods

In certain embodiments, provided herein are methods of treating anindividual in need of an androgen therapy with any pharmaceuticalcomposition or oral dosage form described herein. In some embodiments,provided are methods of treating androdeficiency in an individual inneed thereof by administering to the individual any pharmaceuticalcomposition or dosage form described herein, wherein the pharmaceuticalcomposition or dosage form described herein comprises a therapeuticallyeffective amount of a steroidal compound (e.g., one or more testosteronealkyl ester, such as testosterone undecanoate). In some embodiments,individuals are androdeficient (e.g., hypogonadal, andropausal, orotherwise androdeficient) adult male humans, young male humans who aresuffering from delayed puberty (e.g., as a result of being hypogonadal),androdeficient (e.g., postmenopausal or otherwise androdeficient) adultfemale humans.

In specific embodiments, provided herein are methods of treatingtestosterone deficiency in male humans by administering to the malehuman any pharmaceutical composition or dosage form described herein,wherein the pharmaceutical composition or dosage form described hereincomprises a therapeutically effective amount of one or more testosteronealkyl ester (e.g., testosterone undecanoate). In more specificembodiments, provided herein are methods of treating testosteronedeficiency in hypogonadal male humans (e.g., adult or prepubescent malehumans) by administering to the hypogonadal male human anypharmaceutical composition or dosage form described herein, wherein thepharmaceutical composition or dosage form described herein comprises atherapeutically effective amount of one or more testosterone alkyl ester(e.g., testosterone undecanoate). Symptoms of testosterone deficiencymay include, by way of non-limiting example, one or more of depression,reduced libido, low energy, anemia, osteoporosis, debilitating muscleweakness, or the like. Therefore, in some embodiments, such symptoms,when caused by or suspected of being caused by andro- or testosteronedeficiency, are also treated, either individually or collectively, byadministering to a male human in need thereof a pharmaceuticalcomposition or oral dosage form described herein. In some embodiments,provided herein are methods of treating testosterone deficiency in malehumans by administering to the male human any pharmaceutical compositionor dosage form described herein, wherein the pharmaceutical compositionor dosage form described herein comprises a therapeutically effectiveamount of one or more testosterone alkyl ester (e.g., testosteroneundecanoate) co-administered with a 5-alpha reductase enzyme inhibitor(e.g. dutasteride, finesteride, isotertinoin, gallic acid, L-lysine,epigallocatechin gallate, saw palmetto, phytosterol complex, betasitosterol, green tea extract, polyphenols etc.). In more specificembodiments, the enzyme inhibitor can be co-administered as a separatecomposition or be a part of the same testosterone alkyl ester-containingcomposition.

In some embodiments, provided herein are methods of treating sexualdysfunction in an individual in need thereof by administering theindividual any pharmaceutical composition or dosage form describedherein, wherein the pharmaceutical composition or dosage form describedherein comprises a therapeutically effective amount of a steroidalcompound (e.g., one or more testosterone alkyl ester, such astestosterone undecanoate). In certain embodiments, the individual is amale adult human. In some embodiments, the individual is a female adulthuman.

In specific embodiments, provided herein are methods of treatingandro-deficiency in female humans (e.g., adult female humans) byadministering to the female human any pharmaceutical composition ordosage form described herein, wherein the pharmaceutical composition ordosage form described herein comprises a therapeutically effectiveamount of one or more testosterone alkyl ester (e.g., testosteroneundecanoate). In some embodiments, provided herein are methods ofmaintaining muscle and/or bone mass in female humans (e.g., adult femalehumans) by administering to the female human any pharmaceuticalcomposition or dosage form described herein, wherein the pharmaceuticalcomposition or dosage form described herein comprises a therapeuticallyeffective amount of one or more testosterone alkyl ester (e.g.,testosterone undecanoate).

Provided in various embodiments of the methods described herein,administered are pharmaceutical compositions comprising therapeuticallyeffective amounts of one or more steroidal compound (e.g., one or moretestosterone alkyl ester, such as testosterone undecanoate). In someembodiments, a therapeutically effective amount is between about 1 mgand about 1 g, or about 10 mg to about 200 mg of one or more steroidalcompound (e.g., one or more testosterone alkyl ester, such astestosterone undecanoate). In specific embodiments, a therapeuticallyeffective amount is about 10 mg to about 50 mg, about 15 mg to about 40mg, about 20 mg, to about 30 mg, or about 25 mg of one or more steroidalcompound (e.g., one or more testosterone alkyl ester, such astestosterone undecanoate). In other embodiments, a therapeuticallyeffective amount is about 70 mg to about 150 mg, about 80 mg to about140 mg, about 90 mg to about 140 mg, about 100 mg to about 130 mg, about110 mg to about 130 mg, or about 120 mg of one or more steroidalcompound (e.g., one or more testosterone alkyl ester, such astestosterone undecanoate). In some embodiments, a therapeuticallyeffective amount is about 0.1 mg to about 5 mg per kg of an individualto whom the oral dosage form is administered. In certain embodiments, atherapeutically effective amount is about 1 mg to about 1 g, about 5 mgto about 500 mg, about 10 mg to about 300 mg, or about 20 to about 250mg of a steroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) per day.

In certain embodiments, the methods described herein a plasma C_(max) oftestosterone that is less than 1500 ng/dL, about 100 ng/dL to about 1500ng/dL, or about 500 ng/dL to about 1500 ng/dL in at least 85% of apopulation of individuals (following administration of a single doseand/or in the steady state). In some embodiments the methods describedherein provide a plasma C_(max) of testosterone that is less than 1800ng/dL, about 100 ng/dL to about 1800 ng/dL, or about 500 ng/dL to about1800 ng/dL in at least 95% of a population of individuals (followingadministration of a single dose and/or in the steady state). In someembodiments, the methods described herein provide a plasma C_(max) oftestosterone that is less than 2500 ng/dL, or about 100 ng/dL to 2500ng/dL in all individuals (following administration of a single doseand/or in the steady state). In certain embodiments, the methodsdescribed herein provide a plasma concentration of testosterone atsteady state that is between about 200 ng/dL and 1300 ng/dL in at least75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least99% of a population of individuals. In some embodiments, the methodsdescribed herein provide a plasma concentration of testosterone atsteady state that is between about 200 ng/dL and 1100 ng/dL in at least75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least99% of a population of individuals. In certain embodiments, the methodsdescribed herein provide a plasma concentration of testosterone atsteady state that is between about 300 ng/dL and 1000 ng/dL in at least50%, at least 60%, at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 95%, or at least 99% of a population ofindividuals. Similarly, in various embodiments, the methods describedherein provide any of the pharmacokinetic or pharmacodynamic profilesdescribed for the pharmaceutical compositions or dosage forms describedherein.

In various embodiments, the pharmaceutical compositions or dosage formsdescribed herein are administered orally. In some embodiments,pharmaceutical compositions described herein comprise or are dividedinto one or more oral dosage forms described herein. Thus, in someembodiments, methods described herein comprise and/or pharmacokinetic orpharmacodynamic profiles described herein are achieved by administrationof a plurality of oral dosage forms simultaneously, sequentially or in asubstantially simultaneous manner. Furthermore, administration ofpharmaceutical compositions or oral dosage forms described herein isachieved in any therapeutically effective manner. In some embodiments,the pharmaceutical composition or oral dosage form is administered oncea day, twice a day, three times a day, four times a day, or the like. Insome embodiments, a pharmaceutical composition or oral dosage formdescribed herein is administered in the fed state. In certainembodiments, a pharmaceutical composition or oral dosage form describedherein is administered with a meal, within 30 minutes of a meal, within1 hour of a meal, or within 2 hours of a meal. In more specificembodiments, a pharmaceutical composition or oral dosage form describedherein is administered with a meal, within 30 minutes after a meal,within 1 hour after a meal, or within 2 hours after a meal. In someembodiments, provided herein is a reduced food effect pharmaceuticalcomposition or dosage form, the pharmaceutical composition or dosageform comprising the components as set forth in any embodiment describedherein. In some embodiments, the reduced food effect pharmaceuticalcomposition or dosage form provides, when orally administered in thefasted state, a maximum plasma concentration (C_(max)) of testosteronethat is at least 90%, at least 80%, at least 70%, at least 60%, at least50%, at least 40%, at least 30%, at least 20%, at least 15%, at least10%, or at least 5% of the maximum plasma concentration (C_(max)) oftestosterone provided when the same or identical pharmaceuticalcomposition or dosage form is administered in the fed state. In certainembodiments, the reduced food effect pharmaceutical composition ordosage form provides, when orally administered in the fasted state, amaximum plasma concentration (C_(max)) of testosterone alkyl ester thatis at least 90%, at least 80%, at least 70%, at least 60%, at least 50%,at least 40%, at least 30%, at least 20%, at least 15%, at least 10%, orat least 5% of the maximum plasma concentration (C_(max)) oftestosterone alkyl ester provided when the same or identicalpharmaceutical composition or dosage form is administered in the fedstate. In some embodiments, the reduced food effect pharmaceuticalcomposition or dosage form provides, when orally administered in thefasted state, a maximum plasma concentration (C_(max)) ofdihydrotestosterone that is at least 90%, at least 80%, at least 70%, atleast 60%, at least 50%, at least 40%, at least 30%, at least 20%, atleast 15%, at least 10%, or at least 5% of the maximum plasmaconcentration (C_(max)) of dihydrotestosterone provided when the same oridentical pharmaceutical composition or dosage form is administered inthe fed state.

In certain embodiments, provided herein is a method of treating androgendeficiency in an individual, or a disorder associated therewith, themethod comprising administering to an individual in need thereof atherapeutically effective amount of any composition described herein. Insome embodiments, a composition administered according to a methoddescribed herein is formulated so as to provide any pharmacokineticand/or pharmacodynamic effect described herein. In certain embodiments,methods provided herein comprise the administration of a sufficientamount of a composition described herein so as to provide anypharmacokinetic or pharmacodynamic effect described herein. In variousembodiments, any protocol described herein for the administration ofcompositions is optionally utilized in any methods described herein.

Carriers

Provided herein are pharmaceutical compositions comprising a steroidalcompound (e.g., one or more testosterone alkyl ester, such astestosterone undecanoate) and at least one pharmaceutically acceptablecarrier. In certain embodiments, the at least one pharmaceuticallyacceptable carrier comprises at least one hydrophilic carrier (e.g.,hydrophilic surfactant or additive), at least one lipophilic carrier(e.g., lipophilic surfactant or additive), and/or at least one viscosityenhancer or solidifying agent. In specific embodiments, the at least onepharmaceutically acceptable carrier is a hydrophilic carrier. In morespecific embodiments, the at least one pharmaceutically acceptablecarrier comprises or further comprises a lipophilic carrier. In furtherembodiments, the at least one pharmaceutically acceptable carriercomprises at least one hydrophilic carrier, at least one lipidic and/orlipophilic carrier, and at least one viscosity enhancer or solidifyingagent.

In certain embodiments, hydrophilic carriers include, by way ofnon-limiting example, a hydrophilic surfactant. In various instances,hydrophilic surfactants are used to provide any one or more of severaladvantageous characteristics to the compositions, including, by way ofnon-limiting example: increased solubility of the active ingredient inat least one of the fractions of the carrier that is a solid carrier;improved dissolution of the active ingredient; improved dispersionand/or dissolution of the lipidic carrier; improved solubilization ofthe active ingredient upon dissolution; enhanced absorption and/orbioavailability of the active ingredient, particularly a hydrophilic,hydrophobic, or lipophilic active ingredient; and improved stability,both physical and chemical, of the active ingredient. In variousembodiments, the hydrophilic surfactant includes either a singlehydrophilic surfactant or a mixture of hydrophilic surfactants.Hydrophilic surfactants also include both ionic or non-ionicsurfactants.

In some embodiments, lipophilic carriers include or further include, byway of non-limiting example, one or more lipophilic surfactant,including one or more lipophilic surfactant, one or more mono-, di-, ortriglyceride, or mixtures thereof. In various instances, lipophilicsurfactants provide any one or more of the advantageous characteristicslisted above for hydrophilic surfactants, and/or enhance the function ofother (e.g., hydrophilic) surfactants present in the pharmaceuticalcomposition.

The terms “hydrophilic” and “lipophilic” are relative terms.Hydrophilicity and/or lipophilicity are determined in any mannersuitable. In one instances, an empirical parameter is used tocharacterize the relative hydrophilicity and lipophilicity of thecarriers described herein. For example, in one manner, thehydrophilicity and/or lipophilicity non-ionic amphiphilic compounds isthe hydrophilic-lipophilic balance (the “HLB” value). Carriers orsurfactants with lower HLB values are more lipophilic, and have greatersolubility in oils, whereas surfactants with higher HLB values are morehydrophilic, and have greater solubility in aqueous mediums. Thismeasure is suitable for the surfactants described herein because,generally, surfactants are amphiphilic as they comprise both a polarmoiety (e.g., a polar non-charged or charged moiety) and a lipophilicmoiety (e.g., an aliphatic group).

Using HLB values as a rough guide, hydrophilic surfactants are generallyconsidered to be those compounds having an HLB value greater than about10, as well as non-ionic, anionic, cationic, or zwitterionic compoundsfor which the HLB scale is not generally applicable. Similarly,lipophilic surfactants are compounds having an HLB value less than about10.

It should be appreciated that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions. For many important surfactants,including several polyethoxylated surfactants, it has been reported thatHLB values can differ by as much as about 8 HLB units, depending uponthe empirical method chosen to determine the HLB value (Schott, J.Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certainpolypropylene oxide containing block copolymers (poloxamers, availablecommercially as PLURONIC® surfactants, BASF Corp.), the HLB values arenot always authoritative indicators of the true physical chemical natureof the compounds. Finally, commercial surfactant products are generallynot pure compounds, but are often complex mixtures of compounds, and theHLB value reported for a particular compound may more accurately becharacteristic of the commercial product of which the compound is amajor component. Different commercial products having the same primarysurfactant component can, and typically do, have different HLB values.In addition, a certain amount of lot-to-lot variability is expected evenfor a single commercial surfactant product. Thus, keeping theseconsiderations involved, a person of ordinary skill in the art is ableto utilize HLB values and the identity of a given product to determinesurfactants for suitable lipophilicity and/or hydrophilicity for use inthe pharmaceutical compositions described herein.

As used herein, useful surfactants include any surfactant that ispharmaceutically acceptable and is suitable for use in a pharmaceuticalcomposition. Suitable surfactants include anionic, cationic,zwitterionic and non-ionic surfactants. Provided herein (e.g., in theTables) are several general classes of surfactants. The HLB values givenin the Tables below generally represent the HLB value as reported by themanufacturer of the corresponding commercial product. In cases wheremore than one commercial product is listed, the HLB value in the Tablesis the value as reported for one of the commercial products, a roughaverage of the reported values, or a value that, in the judgment of thepresent inventors, is more reliable.

Surfactants described in the Tables are illustrative and are provided asnon-limiting examples. For example, refined, distilled or fractionatedsurfactants, purified fractions thereof, or re-esterified fractions, arealso within the scope of surfactants described herein, although they arenot specifically listed in the Tables.

In some embodiments, surfactants described herein include polyoxylatedfatty acids, such as polyethoxylated fatty acids (i.e., PEG-fatty acidesters). Provided in Table 1 is a list of illustrative and non-limitingexamples of polyethoxylated fatty acid monoester surfactants.

TABLE 1 PEG-Fatty Acid Monoester Surfactants COMMERCIAL PRODUCT COMPOUND(Supplier) HLB PEG 4-100 monolaurate Crodet L series (Croda) >9 PEG4-100 monooleate Crodet O series (Croda) >8 PEG 4-100 monostearateCrodet S series (Croda), Myrj Series >6 (Atlas/ICI) PEG 400 distearateCithrol 4DS series (Croda) >10 PEG 100, 200, 300 Cithrol ML series(Croda) >10 monolaurate PEG 100, 200, 300 Cithrol MO series (Croda) >10monooleate PEG 400 dioleate Cithrol 4DO series (Croda) >10 PEG 400-1000Cithrol MS series (Croda) >10 monostearate PEG-1 stearate Nikkol MYS-IEX(Nikko), Coster KI 2 (Condea) PEG-2 stearate Nikkol MYS-2 (Nikko) 4PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5 PEG-4 laurate Mapeg ® 200 ML(PPG), Kessco ® 9.3 PEG 200ML (Stepan), LIPOPEG 2L (LIPO Chem.) PEG-4oleate Mapeg. ® 200 MO (PPG), 8.3 Kessco. ® PEG200 MO (Stepan) PEG-4stearate Kessco ® PEG 200 MS (Stepan), 6.5 Hodag 20 S (Calgene), NikkolMYS-4 (Nikko) PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5 PEG-5 oleateNikkol TMGO-5 (Nikko) 9.5 PEG-6 oleate Algon OL 60 (Auschem SpA), 8.5Kessco ® PEG 300 MO (Stepan), Nikkol MYO-6 (Nikko), Emulgante A6(Condea) PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4 PEG-6 laurateKessco ® PEG300 ML (Stepan) 11.4 PEG-7 laurate Lauridac 7 (Condea) 13PEG-6 stearate Kessco ® PEG300 MS (Stepan) 9.7 PEG-8 laurate Mapeg ® 400ML (PPG), 13 LIPOPEG 4DL(Lipo Chem.) PEG-8 oleate Mapeg ® 400 MO (PPG),12 Emulgante A8 (Condea); Kessco PEG 400 MO (Stepan) PEG-8 stearateMapeg ® 400 MS (PPG), Myrj 45 12 PEG-9 oleate Emulgante A9 (Condea) >10PEG-9 stearate Cremophor 59 (BASF) >10 PEG-10 laurate Nikkol MYL-10(Nikko), 13 Lauridac 10 (Croda) PEG-10 oleate Nikkol MYO-10 (Nikko) 11PEG-10 stearate Nikkol MYS-10 (Nikko), 11 Coster K100 (Condea) PEG-12laurate Kessco ® PEG 600ML (Stepan) 15 PEG-12 oleate Kessco ® PEG 600MO(Stepan) 14 PEG-12 ricinoleate (CAS #9004-97-1) >10 PEG-12 stearateMapeg ® 600 MS (PPG), 14 Kessco ® PEG 600MS (Stepan) PEG-15 stearateNikkol TMGS-15 (Nikko), 14 Koster K15 (Condea) PEG-15 oleate NikkolTMGO-15 (Nikko) 15 PEG-20 laurate Kessco ® PEG 1000 ML (Stepan) 17PEG-20 oleate Kessco ® PEG 1000 MO (Stepan) 15 PEG-20 stearate Mapeg ®1000 MS (PPG), 16 Kessco ® PEG 1000 MS (Stepan), Myrj 49 PEG-25 stearateNikkol MYS-25 (Nikko) 15 PEG-32 laurate Kessco ® PEG 1540 ML (Stepan) 16PEG-32 oleate Kessco ® PEG 1540 MO (Stepan) 17 PEG-32 stearate Kessco ®PEG 1540 MS (Stepan) 17 PEG-30 stearate Myrj 51 >10 PEG-40 laurateCrodet L40 (Croda) 17.9 PEG-40 oleate Crodet O40 (Croda) 17.4 PEG-40stearate Myrj 52, Emerest ® 2715 (Henkel), >10 Nikkol MYS-40 (Nikko)PEG-45 stearate Nikkol MYS-45 (Nikko) 18 PEG-50 stearate Myrj 53 >10PEG-55 stearate Nikkol MYS-55 (Nikko) 18 PEG-100 oleate Crodet 0-100(Croda) 18.8 PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19 PEG-200oleate Albunol 200 MO (Taiwan Surf.) >10 PEG-400 oleate LACTOMUL(Henkel), >10 Albunol 400 MO (Taiwan Surf.) PEG-600 oleate Albunol 600MO (Taiwan Surf) >10

Furthermore, in some embodiments, surfactants described herein include,by way of non-limiting example, polyethylene glycol (PEG) fatty aciddiesters. Illustrative and non-limiting examples of PEG-fatty aciddiesters are shown in Table 2.

TABLE 2 PEG-Fatty Acid Diester Surfactants COMMERCIAL PRODUCT COMPOUND(Supplier) HLB PEG-4 dilaurate Mapeg ® 200 DL (PPG), 7 Kessco ® PEG 200DL (Stepan), LIPOPEG 6 2-DL (Lipo Chem.) PEG-4 dioleate Mapeg ® 200 DO(PPG), 6 PEG-4 distearate Kessco ® 200 DS (Stepan) 5 PEG-6 dilaurateKessco ® PEG 300 DL (Stepan) 9.8 PEG-6 dioleate Kessco ® PEG 300 DO(Stepan) 7.2 PEG-6 distearate Kessco ® PEG 300 DS (Stepan) 6.5 PEG-8dilaurate Mapeg ® 400 DL (PPG), 11 Kessco ® PEG 400 DL (Stepan), LIPOPEG4 DL (Lipo Chem.) PEG-8 dioleate Mapeg ® 400 DO (PPG), 8.8 Kessco ® PEG400 DO (Stepan), LIPOPEG 4 DO(Lipo Chem.) PEG-8 distearate Mapeg ® 400DS (PPG), CDS 400 (Nikkol) 11 PEG-10 dipalmitate Polyaldo 2PKFG >10PEG-12 dilaurate Kessco ® PEG 600 DL (Stepan) 11.7 PEG-12 distearateKessco ® PEG 600 DS (Stepan) 10.7 PEG-12 dioleate Mapeg ® 600 DO (PPG),10 Kessco ® 600 DO(Stepan) PEG-20 dilaurate Kessco ® PEG 1000 DL(Stepan) 15 PEG-20 dioleate Kessco ® PEG 1000 DO (Stepan) 13 PEG-20distearate Kessco ® PEG 1000 DS (Stepan) 12 PEG-32 dilaurate Kessco ®PEG 1540 DL (Stepan) 16 PEG-32 dioleate Kessco ® PEG 1540 DO (Stepan) 15PEG-32 distearate Kessco ® PEG 1540 DS (Stepan) 15 PEG-400 dioleateCithrol 4DO series (Croda) >10 PEG-400 distearate Cithrol 4DS series(Croda) >10

As discussed above, in some embodiments, pharmaceutical compositionsdescribed herein comprise mixtures of surfactants, including, e.g.,mixtures of two or more commercial surfactant products. SeveralPEG-fatty acid esters are marketed commercially as mixtures or mono- anddiesters. Illustrative and non-limiting examples of surfactant mixturesare shown in Table 3.

TABLE 3 PEG-Fatty Acid Mono-and Diester Mixtures COMMERCIAL PRODUCTCOMPOUND (Supplier) HLB PEG 4-150 mono, Kessco ® PEG 200-6000 mono,dilaurate dilaurate (Stepan) PEG 4-150 mono, Kessco ® PEG 200-6000 mono,dioteate dioleate (Stepan) PEG 4-150 mono, Kessco ® 200-6000 mono,distearate distearate (Stepan)

In some embodiments, surfactants described herein include, by way ofnon-limiting example, polyethylene glycol glycerol fatty acid esters(PEG glycerol fatty acid esters). Illustrative and non-limiting examplesof PEG glycerol fatty acid esters are shown in Table 4.

TABLE 4 PEG Glycerol Fatty Acid Esters COMMERCIAL PRODUCT COMPOUND(Supplier) HLB PEG-20 glyceryl laurate Tagat ® L (Goldschmidt) 16 PEG-30glyceryl laurate Tagat ® L2 (Goldschmidt) 16 PEG-15 glyceryl laurateGlycerox L series (Croda) 15 PEG-40 glyceryl laurate Glycerox L series(Croda) 15 PEG-20 glyceryl stearate Capmul ® EMG (ABITEC), 13 Aldo ®MS-20 KFG (Lonza) PEG-20 glyceryl oleate Tagat ® O (Goldschmidt) >10PEG-30 glyceryl oleate Tagat ® O2 (Goldschmidt) >10

In certain embodiments, surfactants of different degrees oflipophilicity or hydrophilicity are prepared by reaction of alcohols orpolyalcohols with a variety of natural and/or hydrogenated oils. In someembodiments, the oils used are castor oil or hydrogenated castor oil oran edible vegetable oil such as corn oil, olive oil, peanut oil, palmkernel oil, apricot kernel oil, or almond oil. In specific embodiments,alcohols include glycerol, propylene glycol, ethylene glycol,polyethylene glycol, sorbitol, and pentaerythritol. In certainembodiments, such surfactants are utilized in the pharmaceuticalcompositions described herein. Illustrative and non-limiting examples ofsurfactants of this class suitable for use in the pharmaceuticalcompositions described herein are shown in Table 5.

TABLE 5 Transesterification Products of Oils and Alcohols COMMERCIALPRODUCT COMPOUND (Supplier) HLB PEG-3 castor oil Nikkol CO-3 (Nikko) 3PEG-5, 9, and 16 ACCONON CA series (ABITEC) 6-7 castor oil PEG-20 castoroil Emalex C-20 (Nihon Emulsion), 11 Nikkol CO-20 TX (Nikko) PEG-23castor oil Emulgante EL23 >10 PEG-30 castor oil Emalex C-30 (NihonEmulsion), 11 Alkamuls ® EL 620 (Rhone- Poulenc), Incrocas 30 (Croda)PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35(Croda), Emulgin RO 35 (Henkel) PEG-38 castor oil Emulgante EL 65(Condea) PEG-40 castor oil Emalex C-40 (Nihon Emulsion), 13 Alkamuls ®EL 719 (Rhone- Poulenc) PEG-50 castor oil Emalex C-50 (Nihon Emulsion)14 PEG-56 castor oil Eumulgin ® PRT 56 (Pulcra SA) >10 PEG-60 castor oilNikkol CO-60TX (Nikko) 14 PEG-100 castor oil Thornley >10 PEG-200 castoroil Eumulgin ® PRT 200 (Pulcra SA) >10 PEG-5 hydrogenated Nikkol HCO-5(Nikko) 6 castor oil PEG-7 hydrogenated Simusol ® 989 (Seppic), 6 castoroil Cremophor WO7 (BASF) PEG-10 hydrogenated Nikkol HCO-10 (Nikko) 6.5castor oil PEG-20 hydrogenated Nikkol HCO-20 (Nikko) 11 castor oilPEG-25 hydrogenated Simulsol ® 1292 (Seppic), 11 castor oil Cerex ELS250 (Auschem SpA) PEG-30 hydrogenated Nikkol HCO-30 (Nikko) 11 castoroil PEG-40 hydrogenated Cremophor RH 40 (BASF), 13 castor oil Croduret(Croda), Emulgin HRE 40 (Henkel) PEG-45 hydrogenated Cerex ELS 450(Auschem Spa) 14 castor oil PEG-50 hydrogenated Emalex HC-50 (NihonEmulsion) 14 castor oil PEG-60 hydrogenated Nikkol HCO-60 (Nikko); 15castor oil Cremophor RH 60 (BASF) PEG-80 hydrogenated Nikkol HCO-80(Nikko) 15 castor oil PEG-100 Nikkol HCO-100 (Nikko) 17 hydrogenatedcastor oil PEG-6 corn oil Labrafil ® M 2125 CS (Gattefosse) 4 PEG-6almond oil Labrafil ® M 1966 CS (Gattefosse) 4 PEG-6 apricot Labrafil ®M 1944 CS (Gattefosse) 4 kernel oil PEG-6 olive oil Labrafil ® M 1980 CS(Gattefosse) 4 PEG-6 peanut oil Labrafil ® M 1969 CS (Gattefosse) 4PEG-6 hydrogenated Labrafil ® M 2130 BS (Gattefosse) 4 palm kernel oilPEG-6 palm kernel oil Labrafil ® M 2130 CS (Gattefosse) 4 PEG-6 trioleinLabrafil ® M 2735 CS (Gattefosse) 4 PEG-8 corn oil Labrafil ® WL 2609 BS(Gattefosse) 6-7 PEG-20 corn Crovol M40 (Croda) 10 glycerides PEG-20almond Crovol A40 (Croda) 10 glycerides PEG-25 trioleate TAGAT ® TO(Goldschmidt) 11 PEG-40 palm Crovol PK-70 >10 kernel oil PEG-60 cornCrovol M70(Croda) 15 glycerides PEG-60 almond Crovol A70 (Croda) 15glycerides PEG-4 caprylic/capric Labrafac ® Hydro (Gattefosse), 4-5triglyceride PEG-8 caprylic/capric Labrasol (Gattefosse), >10 glyceridesLabrafac CM 10 (Gattefosse) PEG-6 caprylic/capric SOFTIGEN ® 767 (Hüls),19 glycerides Glycerox 767 (Croda) Lauroyl macrogol-32 GELUCIRE 44/14(Gattefosse) 14 glyceride Stearoyl macrogol GELUCIRE 50/13 (Gattefosse)13 glyceride Mono, di, tri, tetra SorbitoGlyceride (Gattefosse) <10esters of vegetable oils and sorbitol Pentaerythrityl Crodamol PTIS(Croda) <10 tetraisostearate Pentaerythrityl Albunol DS (Taiwan Surf.)<10 distearate Pentaerythrityl Liponate PO-4 (Lipo Chem.) <10tetraoleate Pentaerythrityl Liponate PS-4 (Lipo Chem.) <10 tetrastearatePentaerythrityl Liponate PE-810 (Lipo Chem.), <10 tetracaprylate/Crodamol PTC (Croda) tetracaprate Pentaerythrityl Nikkol Pentarate 408(Nikko) tetraoctanoate

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include, by way of non-limiting example,polyglycerized fatty acids. Illustrative and non-limiting examples ofsuitable polyglyceryl esters are shown in Table 6.

TABLE 6 Polyglycerized Fatty Acids COMMERCIAL PRODUCT COMPOUND(Supplier) HLB Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2 isostearateNikkol DGMIS (Nikko) 5-7 Polyglyceryl-3 oleate Caprol ® 3G0 (ABITEC),6.5 Drewpol 3-1-O (Stepan) Polyglyceryl-4 oleate Nikkol Tetraglyn 1-O(Nikko) 5-7 Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S (Nikko) 5-6Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan), 9 Nikkol Hexaglyn 1-O(Nikko) Polyglyceryl-10 laurate Nikkol Decaglyn 1-L (Nikko) 15Polyglyceryl-10 oleate Nikkol Decaglyn 1-O (Nikko) 14 Polyglyceryl-10stearate Nikkol Decaglyn 1-S (Nikko) 12 Polyglyceryl-6 ricinoleateNikkol Hexaglyn PR-15 (Nikko) Polyglyceryl-10 linoleate Nikkol DecaglynI-LN (Nikko) 12 Polyglyceryl-6 pentaoleate Nikkol Hexaglyn S-O (Nikko)<10 Polyglyceryl-3 dioleate Cremophor G032 (BASF) <10 Polyglyceryl-3distearate Cremophor GS32 (BASF) <10 Polyglyceryl-4 pentaoleate NikkolTetraglyn 5-O (Nikko) <10 Polyglyceryl-6 dioleate Caprol ® 6G20 8.5(ABITEC); Hodag PGO-62 (Calgene), PLUROL OLEIQUE CC 497 (Gattefosse)Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7 Polyglyceryl-10 trioleateNikkol Decaglyn 3-O (Nikko) 7 Polyglyceryl-10 pentaoleate NikkolDecaglyn 5-O (Nikko) 3.5 Polyglyceryl-10 septaoleate Nikkol Decagtyn 7-O(Nikko) 3 Polyglyceryl-10 tetraoleate Caprol ® 10G40 (ABITEC); 6.2 HodagPGO-62 (CALGENE), Drewpol 10-4-O (Stepan) Polyglyceryl-10decaisostearate Nikkol Decaglyn 10-IS (Nikko) <10 Polyglyceryl-10decaoleate Drewpol 10-10-O (Stepan), 3.5 Caprol 10G10O (ABITEC), NikkolDecaglyn 10-O Polyglyceryl-10 mono, Caprol ® PGE 860 (ABITEC) 11dioleate Polyglyceryl polyricinoIeate Polymuls (Henkel)  3-20

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include, by way of non-limiting exampleesters of propylene glycol and fatty acids. Illustrative andnon-limiting examples of surfactants of this class are given in Table 7.

TABLE 7 Propylene Glycol Fatty Acid Esters COMMERCIAL PRODUCT COMPOUND(Supplier) HLB Propylene glycol monocaprylate Capryol 90 (Gattefosse),<10 Nikkol Sefsol 218 (Nikko) Propylene glycol monolaurate Lauroglycol90 (Gattefosse), <10 Lauroglycol FCC (Gattefosse) Propylene glycololeate Lutrol OP2000 (BASF) <10 Propylene glycol myristate Mirpyl <10Propylene glycol monostearate ADM PGME-03 (ADM), 3-4 LIPO PGMS (LipoChem.), Aldo ® PGHMS (Lonza) Propylene glycol hydroxy stearate <10Propylene glycol ricinoleate PROPYMULS (Henkel) <10 Propylene glycolisostearate <10 Propylene glycol monooleate Myverol P-06 (Eastman) <10Propylene glycol Captex ® >6 dicaprylate/dicaprate 200 (ABITEC),Miglyol ® 840 (Huls), Neobee ® M-20 (Stepan) Propylene glycoldioctanoate Captex ® 800 (ABITEC) Propylene glycol LABRAFAC >6caprylate/caprate PG (Gattefosse) Propylene glycol dilaurate >6Propylene glycol distearate Kessco ® PGDS (Stepan) >6 Propylene glycoldicaprylate Nikkol Sefsol 228 (Nikko) >6 Propylene glycol dicaprateNikkol PDD (Nikko) >6

As discussed above, mixtures of surfactants are also used, in someembodiments, in the pharmaceutical compositions described herein.Mixtures of surfactants include, by way of non-limiting example,mixtures of propylene glycol fatty acid esters and glycerol fatty acidesters are suitable and are commercially available. Illustrative andnon-limiting examples of such mixtures of surfactants include, by way ofnon-limiting example, those shown in Table 8.

TABLE 8 Glycerol/Propylene Glycol Fatty Acid Esters COMMERCIAL PRODUCTCOMPOUND (Supplier) HLB Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4 StearicATMOS 150 3-4

In certain embodiments, an important class of surfactants includes theclass of mono- and diglycerides. These surfactants are generallylipophilic. Illustrative and non-limiting examples of these surfactantsare given in Table 9.

TABLE 9 Mono- and Diglyceride Surfactants COMMERCIAL PRODUCT COMPOUND(Supplier) HLB Monopalmitolein (C16:1) (Larodan) <10 Monoelaidin (C18:1)(Larodan) <10 Monocaproin (C6) (Larodan) <10 Monocaprylin (Larodan) <10Monocaprin (Larodan) <10 Monolaurin (Larodan) <10 Glyceryl Nikkol MGM(Nikko) 3-4 monomyristate (C14) Glyceryl monooleate PECEOL (Gattefosse),3-4 (C18:1) Hodag GMO-D, Nikkol MGO (Nikko) Glyceryl monooleate RYLOseries (Danisco), 3-4 DIMODAN series (Danisco), EMULDAN (Danisco),ALDO ® MO FG (Lonza), Kessco GMO (Stepan), MONOMULS ® series (Henkel),TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80(Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol (Eastman) Glycerolmonooleate/ OLICINE (Gattefosse) 3-4 linoleate Glycerol monolinoleateMaisine (Gattefosse), 3-4 MYVEROL 18-92, Myverol 18-06 (Eastman)Glyceryl Softigen ® 701 (Huls), 6 ricinoleate HODAG GMR-D (Calgene),ALDO ® MR (Lonza) Glyceryl ALDO ® MLD (Lonza), 6.8 monolaurate Hodag GML(Calgene) Glycerol monopalmitate Emalex GMS-P (Nihon) 4 GlycerolCapmul ® GMS. (ABITEC), 5-9 monostearate Myvaplex (Eastman), IMWITOR ®191 (Hüls), CUTINA GMS, Aldo ® MS (Lonza), Nikkol MGS series (Nikko)Glyceryl Capmul ® GMO-K (ABITEC) <10 mono-, dioleate Glyceryl CUTINAMD-A, ESTAGEL-G18 <10 palmitic/stearic Glyceryl acetate Lamegin ® EE(Grünau GmbH) <10 Glyceryl laurate Inwitor ® 312 (Hüls), 4 Monomuls ®90-45 (Grünau GmbH), Aldo ® MLD (Lonza) Glyceryl citrate/ Imwitor ® 375(Hüls) <10 lactate/oleate/linoieate Glyceryl caprylate Imwitor ® 308(Hüls), 5-6 Capmul ® MCMC8 (ABITEC) Glyceryl Capmul ® MCM (ABITEC) 5-6caprylate/caprate Caprylic acid mono, Imwitor ® 988 (Hüls) 5-6diglycerides Caprylic/capric Imwitor ® 742 (Hüls) <10 glyceridesMono-and diacetylated Myvacet ® 9-45, 3.8-4   monoglycerides Myvacet ®9-40, Myvacet ® 9-08 (Eastman), Lamegin ® (Grünau) Glyceryl monostearateAldo ® MS, Arlacel 129 (ICI), 4.4 LIPO GMS (Lipo Chem.), Imwitor ® 191(Huls), Myvaplex (Eastman) Lactic acid esters of LAMEGIN GLP (Henkel)<10 mono, diglycerides Dicaproin (C6) (Larodan) <10 Dicaprin (C10)(Larodan) <10 Dioctanoin (C8) (Larodan) <10 Dimyristin (C14) (Larodan)<10 Dipalmitin (C16) (Larodan) Distearin (Larodan) <10 Glyceryldilaurate (C12) Capmul ® GDL (ABITEC) 3-4 Glyceryl dioleate Capmul ® GDO(ABITEC) 3-4 Glycerol esters of GELUCIRE 39/01 (Gattefosse), 1 fattyacids GELUCIRE 43/01 (Gattefosse) 6 GELUCIRE 37/06 (Gattefosse)Dipalmitolein (C16:1) (Larodan) 1,2 and 1,3-diolein (C18:1) (Larodan)<10 Dielaidin (C18:1) (Larodan) <10 Dilinolein (C18:2) (Larodan) <10

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include sterols and derivatives ofsterols. In various embodiments, these surfactants are hydrophilic orlipophilic. Illustrative and non-limiting examples of surfactants ofthis class are shown in Table 10.

TABLE 10 Sterol and Sterol Derivative Surfactants COMMERCIAL PRODUCTCOMPOUND (Supplier) HLB Cholesterol, sitosterol, <10 lanosterol PEG-24cholesterol ether Solulan C-24 (Amerchol) >10 PEG-30 cholestanol NikkolDHC (Nikko) >10 Phytosterol GENEROL series (Henkel) <10 PEG-25 phytosterol Nikkol BPSH-25 (Nikko) >10 PEG-5 soya sterol Nikkol BPS-S (Nikko)<10 PEG-10 soya sterol Nikkol BPS-10 (Nikko) <10 PEG-20 soya sterolNikkol BPS-20 (Nikko) <10 PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10

In some embodiments, surfactants useful in the pharmaceuticalcompositions described herein include a variety of PEG-sorbitan fattyacid esters. In general, these surfactants are hydrophilic, althoughseveral lipophilic surfactants of this class can be used. Illustrativeand non-limiting examples of these surfactants are shown in Table 11.

TABLE 11 PEG-Sorbitan Fatty Acid Esters COMMERCIAL PRODUCT COMPOUND(Supplier) HLB PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI), 17 Crillet 1 (Croda),DACOL MLS 20 (Condea) PEG-4 sorbitan monolaurate Tween-21 (Atlas/ICI),13 Crillet 11 (Croda) PEG-80 sorbitan monolaurate Hodag PSML-80(Calgene); >10 T-Maz 28 PEG-6 sorbitan monolaurate Nikkol GL-1 (Nikko)16 PEG-20 sorbitan monopalmitate Tween-40 (Atlas/ICI), 16 Crillet 2(Croda) PEG-20 sorbitan monostearate Tween-60 (Atlas/ICI), 15 Crillet 3(Croda) PEG-4 sorbitan monostearate Tween-61 (Atlas/ICI), 9.6 Crillet 31(Croda) PEG-8 sorbitan monostearate DACOL MSS (Condea) >10 PBG-6sorbitan monostearate Nikkol TS106 (Nikko) 11 PEG-20 sorbitantristearate Tween-65 (Atlas/ICI), 11 Crillet 35 (Croda) PEG-6 sorbitantetrastearate Nikkol GS-6 (Nikko) 3 PEG-60 sorbitan tetrastearate NikkolGS-460 (Nikko) 13 PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), 10Crillet 41 (Croda) PEG-6 sorbitan monooleate Nikkol TO-106 (Nikko) 10PEG-20 sorbitan monooleate Tween-80 (Atlas/ICI), 15 Crillet 4 (Croda)PEG-40 sorbitan oleate Emalex ET 8040 18 (Nihon Emulsion) PEG-20sorbitan trioleate Tween-85 (Atlas/ICI), 11 Crillet 45 (Croda) PEG-6sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5 PEG-30 sorbitan tetraoleateNikkol GO-430 (Nikko) 12 PEG-40 sorbitan tetraoleate Nikkol GO-440(Nikko) 13 PEG-20 monoisostearate sorbitan Tween-120 (Atlas/ICI), >10Crillet 6 (Croda) PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10 PEG-6sorbitol hexastearate Nikkol GS-6 (Nikko) 3

In some embodiments, surfactants utilized herein include ethers ofpolyethylene glycol and alkyl alcohols. Illustrative and non-limitingexamples of these surfactants are shown in Table 12.

TABLE 12 Polyethylene Glycol Alkyl Ethers COMMERCIAL PRODUCT COMPOUND(Supplier) HLB PEG-2 oleyl ether, oleth-2 Brij 92/93 (Atlas/ICI) 4.9PEG-3 oleyl ether, oleth-3 Volpo 3 (Croda) <10 PEG-5 oleyl ether,oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl ether, oleth-10 Volpo 10(Croda), 12 Brij 96/97 (Atlas/ICI) PEG-20 oleyl ether, oleth-20 Volpo 20(Croda), 15 Brij 98/99 (Atlas/ICI) PEG-4 lauryl ether, laureth-4 Brij 30(Atlas/ICI) 9.7 PEG-9 lauryl ether >10 PEG-23 lauryl ether, laureth-23Brij 35 (Atlas/ICI) 17 PEG-2 cetyl ether Brij 52 (ICI) 5.3 PEG-10 cetylether Brij 56 (ICI) 13 PEG-20 cetyl ether Brij 58 (ICI) 16 PEG-2 stearylether Brij 72 (ICI) 4.9 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-20stearyl ether Brij 78 (ICI) 15 PEG-100 stearyl ether Brij 700 (ICI) >10

In certain embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include esters of sugars. Illustrative andnon-limiting examples of such surfactants are shown in Table 13.

TABLE 13 Sugar Ester Surfactants COMMERCIAL PRODUCT COMPOUND (Supplier)HLB Sucrose distearate SUCRO ESTER 7 (Gattefosse), 3 Crodesta F-10(Croda) Sucrose distearate/ SUCRO ESTER 11 (Gattefosse), 12 monostearateCrodesta F-110 (Croda) Sucrose dipalmitate 7.4 Sucrose monostearateCrodesta F-160 (Croda) 15 Sucrose monopalmitate SUCRO ESTER 15(Gattefosse) >10 Sucrose monolaurate Saccharose monolaurate 15 1695(Mitsubishi-Kasei)

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include polyethylene glycol alkyl phenols,e.g., hydrophilic PEG-alkyl phenol surfactants. Illustrative andnon-limiting examples of these surfactants are shown in Table 14.

TABLE 14 Polyethylene Glycol Alkyl Phenol Surfactants COMMERCIAL PRODUCTCOMPOUND (Supplier) HLB PEG-10-100 Triton X series (Rohm & Haas), >10nonyl phenol Igepal CA series (GAF, USA), PEG-15-100 Antarox CA series(GAF, UK) >10 octyl phenol ether Triton N-series (Rohm & Haas), IgepalCO series (GAF, USA), Antarox CO series (GAF, UK)

In certain embodiments, surfactants utilized in pharmaceuticalcompositions described herein include polyoxyethylene-polyoxypropyleneblock copolymers. POE-POP block copolymers are a unique class ofpolymeric surfactants. The unique structure of the surfactants, withhydrophilic POE and lipophilic POP moieties in well-defined ratios andpositions, provides a wide variety of surfactants suitable for use inthe present invention. These surfactants are available under varioustrade names, including Synperonic PE series (ICI); Pluronic® series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H; wherein the terms “a” and “b”denote the number of polyoxyethylene and polyoxypropylene units,respectively.

Illustrative and non-limiting examples of suitable surfactants of thisclass are shown in Table 15. Since the compounds are widely available,commercial sources are not listed in the Table. The compounds are listedby generic name, with the corresponding “a” and “b” values.

TABLE 15 POE-POP Block Copolymers a, b values in COMPOUNDHO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a) H HLB Poloxamer 105 a = 11; b = 16 8Poloxamer 108 a = 46; b = 16 >10 Poloxamer 122  a = 5; b = 21 3Poloxamer 123  a = 7; b = 21 7 Poloxamer 124 a = 11; b = 21 >7 Poloxamer181  a = 3; b = 30 Poloxamer 182  a = 8; b = 30 2 Poloxamer 183 a = 10;b = 30 Poloxamer 184 a = 13; b = 30 Poloxamer 185 a = 19; b = 30Poloxamer 188 a = 75; b = 30 29 Poloxamer 212  a = 8; b = 35 Poloxamer215 a = 24; b = 35 Poloxamer 217 a = 52; b = 35 Poloxamer 231 a = 16; b= 39 Poloxamer 234 a = 22; b = 39 Poloxamer 235 a = 27; b = 39 Poloxamer237 a = 62; b = 39 24 Poloxamer 238 a = 97; b = 39 Poloxamer 282 a = 10;b = 47 Poloxamer 284 a = 21; b = 47 Poloxamer 288 a = 122; b = 47  >10Poloxamer 331  a = 7; b = 54 0.5 Poloxamer 333 a = 20; b = 54 Poloxamer334 a = 31; b = 54 Poloxamer 335 a = 38; b = 54 Poloxamer 338 a = 128; b= 54  Poloxamer 401  a = 6; b = 67 Poloxamer 402 a = 13; b = 67Poloxamer 403 a = 21; b = 67 Poloxamer 407 a = 98; b = 67

In some embodiments, surfactants utilized in pharmaceutical compositionsdescribed herein include sorbitan esters of fatty acids. Illustrativeand non-limiting examples of such surfactants are shown in Table 16.

TABLE 16 Sorbitan Fatty Acid Ester Surfactants COMMERCIAL PRODUCTCOMPOUND (Supplier) HLB Sorbitan monolaurate Span-20 (Atlas/ICI), Crill1 (Croda), 8.6 Arlacel 20 (ICI) Sorbitan monopalmitate Span-40(Atlas/ICI), Crill 2 (Croda), 6.7 Nikkol SP-10 (Nikko) Sorbitanmonooleate Span-80 (Atlas/ICI), Crill 4 (Croda), 4.3 Crill 50 (Croda)Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 (Croda), 4.7 NikkolSS-10 (Nikko) Sorbitan trioleate Span-85 (Atlas/ICI), Crill 45 (Croda),4.3 Nikkol SO-30 (Nikko) Sorbitan sesquioleate Arlacel-C (ICI), Crill 43(Croda), 3.7 Nikkol SO-15 (Nikko) Sorbitan tristearate Span-65(Atlas/ICI) Crill 35 (Croda), 2.1 Nikkol SS-30 (Nikko) Sorbitanmonoisostearate Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7 Sorbitansesquistearate Nikkol SS-15 (Nikko) 4.2

In certain embodiments, surfactants utilized in pharmaceuticalcompositions described herein include esters of lower alcohols (C₂ toC₄) and fatty acids (C₈ to C₁₈). Illustrative and non-limiting examplesof these surfactants are shown in Table 17.

TABLE 17 Lower Alcohol Fatty Acid Ester Surfactants COMMERCIAL PRODUCTCOMPOUND (Supplier) HLB Ethyl oleate Crodamol EO (Croda), <10 Nikkol EOO(Nikko) Isopropyl myristate Crodamol IPM (Croda) <10 Isopropyl palmitateCrodamol IPP (Croda) <10 Ethyl linoleate Nikkol VF-E (Nikko) <10Isopropyl linoleate Nikkol VF-IP (Nikko) <10

In some embodiments, hydrophilic surfactants utilized in pharmaceuticalcompositions described herein include ionic surfactants (e.g., cationic,anionic and zwitterionic surfactants). In specific embodiments, anionicsurfactants include fatty acid salts and bile acid salts. In certainspecific embodiments, cationic surfactants include carnitines. In somespecific embodiments, ionic surfactants include, by way of non-limitingexample, sodium oleate, sodium lauryl sulfate, sodium laurylsarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodiumtaurocholate; lauroyl carnitine; palmitoyl carnitine; and myristoylcarnitine. Illustrative and non-limiting examples of such surfactantsare shown in Table 18. For simplicity, exemplary counterions are shownin the entries in the Table. In various embodiments, such counterionsare optionally substituted with any suitable counterion. For example,although the fatty acids are shown as sodium salts, other cationcounterions are optionally used, such as alkali metal cations orammonium. Unlike certain non-ionic surfactants, these ionic surfactantsare generally available as pure compounds, rather than commercial(proprietary) mixtures. Because these compounds are readily availablefrom a variety of commercial suppliers, such as Aldrich, Sigma, and thelike, commercial sources are not generally listed in the Table.

TABLE 18 Ionic Surfactants COMPOUND HLB FATTY ACID SALTS >10 Sodiumcaproate Sodium caprylate Sodium caprate Sodium laurate Sodium myristateSodium myristolate Sodium palmitate Sodium palmitoleate Sodium oleate 18Sodium ricinoleate Sodium linoleate Sodium linolenate Sodium stearateSodium lauryl sulfate (dodecyl) 40 Sodium tetradecyl sulfate Sodiumlauryl sarcosinate Sodium dioctyl sulfosuccinate [sodium docusate(Cytec)] BILE SALTS >10 Sodium cholate Sodium taurocholate Sodiumglycocholate Sodium deoxycholate Sodium taurodeoxycholate Sodiumglycodeoxycholate Sodium ursodeoxycholate Sodium chenodeoxycholateSodium taurochenodeoxycholate Sodium glyco cheno deoxycholate Sodiumcholylsarcosinate Sodium N-methyl taurocholate Sodium lithocholatePHOSPHOLIPIDS Egg/Soy lecithin [Epikuron ™ (Lucas Meyer), Ovothin ™(Lucas Meyer)] Lyso egg/soy lecithin Hydroxylated lecithinLysophosphatidylcholine Cardiolipin Sphingomyelin PhosphatidylcholinePhosphatidyl ethanolamine Phosphatidic acid Phosphatidyl glycerolPhosphatidyl serine PHOSPHORIC ACID ESTERS Diethanolammoniumpolyoxyethylene-10 oleyl ether phosphate Esterification products offatty alcohols or fatty alcohol ethoxylates with phosphoric acid oranhydride CARBOXYLATES Ether carboxylates (by oxidation of terminal OHgroup of fatty alcohol ethoxylates) Succinylated monoglycerides [LAMEGINZE (Henkel)] Sodium stearyl fumarate Stearoyl propylene glycol hydrogensuccinate Mono/diacetylated tartaric acid esters of mono- anddiglycerides Citric acid esters of mono-, diglycerides Glyceryl-lactoesters of fatty acids (CFR ref. 172.852) Acyl lactylates: lactylicesters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodiumstearoyl lactylate Alginate salts Propylene glycol alginate SULFATES ANDSULFONATES Ethoxylated alkyl sulfates Alkyl benzene sulfones α-olefinsulfonates Acyl isethionates Acyl taurates Alkyl glyceryl ethersulfonates Octyl sulfosuccinate disodium Disodiumundecylenamideo-MEA-sulfosuccinate CATIONIC Surfactants >10 Lauroylcarnitine Palmitoyl carnitine Myristoyl carnitine Hexadecyl triammoniumbromide Decyl trimethyl ammonium bromide Cetyl trimethyl ammoniumbromide Dodecyl ammonium chloride Alkyl benzyldimethylammonium saltsDiisobutyl phenoxyethoxydimethyl benzylammonium salts Alkylpyridiniumsalts Betaines (trialkylglycine): Lauryl betaine(N-lauryl,N,N-dimethylglycine) Ethoxylated amines: Polyoxyethylene-15coconut amine

In some embodiments, surfactants utilized in pharmaceutical compositionsdescribed herein include ionizable surfactants. In certain embodiments,ionizable surfactants, when present in their unionized (neutral,non-salt) form, are lipophilic surfactants suitable for use in thecompositions of the present invention. Particular examples of suchsurfactants include free fatty acids, particularly C₆-C₂₂ fatty acids,and bile acids. More specifically, suitable unionized ionizablesurfactants include the free fatty acid and bile acid forms of any ofthe fatty acid salts and bile salts shown in Table 18.

In some instances, derivatives of oil-soluble vitamins, such as vitaminsA, D, E, K, etc., are also useful surfactants for use in thepharmaceutical compositions described herein. An example of such aderivative is tocopheryl PEG-1000 succinate (TPGS, available fromEastman).

In specific embodiments, surfactants or mixtures of surfactants thatsolidify (e.g., form a solid, a semi-solid, a gel, a jelly, a paste, orthe like) at ambient room temperature are utilized in the pharmaceuticalcompositions described herein. In certain specific embodiments,surfactants or mixtures of surfactants utilized in the pharmaceuticalcompositions described herein solidify (e.g., form a solid, asemi-solid, a gel, a jelly, a paste, or the like) at ambient roomtemperature when combined with additional agents (e.g., particularlipophilic components, such as triglycerides, vitamins (e.g., VitaminE), or the like, viscosity modifiers, stabilizers, solidifying agents,binders, thickeners, or the like). Such additional agents are optionallyutilized in the pharmaceutical compositions described herein. In certainembodiments, pharmaceutical compositions described herein comprise ahydrophilic carrier (e.g., a hydrophilic surfactant), a lipophiliccarrier, and/or a viscosity modifier or solidifying agent.

In some specific embodiments, non-ionic hydrophilic surfactants includealkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylenealkylphenols; polyethylene glycol fatty acids esters; polyethyleneglycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acidesters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerolfatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction mixtures ofpolyols with fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; sugar esters, sugar ethers;sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives;and mixtures thereof.

In certain specific embodiments, the non-ionic hydrophilic surfactant isselected from, by way of non-limiting example, polyoxyethylenealkylethers; polyethylene glycol fatty acids esters; polyethylene glycolglycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fattyacid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils;and polyoxyethylene hydrogenated vegetable oils. In various embodiments,the glyceride is a monoglyceride, diglyceride, triglyceride, or amixture thereof.

In some specific embodiments, non-ionic hydrophilic surfactants are theproducts of reaction mixtures of polyols and fatty acids, glycerides,vegetable oils, hydrogenated vegetable oils or sterols. These reactionmixtures are largely composed of the transesterification products of thereaction, along with often complex mixtures of other reaction products.In more specific embodiments, the polyol is glycerol, ethylene glycol,polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or asaccharide.

In certain specific embodiments, the hydrophilic surfactant is orincludes an ionic surfactant. Specific ionic surfactants include alkylammonium salts; bile acids and salts, analogues, and derivativesthereof; fusidic acid and derivatives thereof; fatty acid derivatives ofamino acids, oligopeptides, and polypeptides; glyceride derivatives ofamino acids, oligopeptides, and polypeptides; acyl lactylates;mono-,diacetylated tartaric acid esters of mono-,diglycerides;succinylated monoglycerides; citric acid esters of mono-,diglycerides;alginate salts; propylene glycol alginate; lecithins and hydrogenatedlecithins; lysolecithin and hydrogenated lysolecithins;lysophospholipids and derivatives thereof; phospholipids and derivativesthereof; salts of alkylsulfates; salts of fatty acids; sodium docusate;carnitines; and mixtures thereof.

In some specific embodiments, ionic surfactants include bile acids andsalts, analogues, and derivatives thereof; lecithins, lysolecithin,phospholipids, lysophospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates;mono-,diacetylated tartaric acid esters of mono-,diglycerides;succinylated monoglycerides; citric acid esters of mono-diglycerides;carnitines; and mixtures thereof. In more specific embodiments, ionicsurfactants include, by way of non-limiting example, lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylglycerol, phosphatidic acid, phosphatidyl serine,lysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine,PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylicesters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate,succinylated monoglycerides, mono/diacetylated tartaric acid esters ofmono/diglycerides, citric acid esters of mono/diglycerides, cholate,taurocholate, glycocholate, deoxycholate, taurodeoxycholate,chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate,taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate,glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate,caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate,linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate,docusate, lauroyl carnitines, palmitoyl carnitines, myristoylcarnitines, and salts and mixtures thereof. In more specificembodiments, ionic surfactants are selected from lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic estersof fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylatedmonoglycerides, mono/diacetylated tartaric acid esters ofmono/diglycerides, citric acid esters of mono/diglycerides, cholate,taurocholate, glycocholate, deoxycholate, taurodeoxycholate,glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate,laurate, oleate, lauryl sulfate, docusate, and salts and mixturesthereof, with the most preferred ionic surfactants being lecithin,lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyllactylate, succinylated monoglycerides, mono/diacetylated tartaric acidesters of mono/diglycerides, citric acid esters of mono/diglycerides,taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, andsalts and mixtures thereof.

In various embodiments, lipophilic surfactants are selected from, by wayof non-limiting example, alcohols; polyoxyethylene alkylethers; fattyacids; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; polyethylene glycol fattyacids esters; polyethylene glycol glycerol fatty acid esters;polypropylene glycol fatty acid esters; polyoxyethylene glycerides;lactic acid derivatives of mono/diglycerides; propylene glycoldiglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fattyacid esters; polyoxyethylene-polyoxypropylene block copolymers;transesterified vegetable oils; sterols; sterol derivatives; sugaresters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils;and polyoxyethylene hydrogenated vegetable oils. As with the hydrophilicsurfactants, lipophilic surfactants are optionally the products ofreaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols. In specific embodiments,lipophilic surfactants are selected from fatty acids; lower alcoholfatty acid esters; polyethylene glycol glycerol fatty acid esters;polypropylene glycol fatty acid esters; polyoxyethylene glycerides;glycerol fatty acid esters; acetylated glycerol fatty acid esters;lactic acid derivatives of mono/diglycerides; sorbitan fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylenevegetable oils; polyoxyethylene hydrogenated vegetable oils; andreaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols. In certain specificembodiments, lipophilic surfactants are selected from lower alcoholfatty acids esters; polypropylene glycol fatty acid esters; propyleneglycol fatty acid esters; glycerol fatty acid esters; acetylatedglycerol fatty acid esters; lactic acid derivatives ofmono/diglycerides; sorbitan fatty acid esters; polyoxyethylene vegetableoils; and mixtures thereof, with glycerol fatty acid esters andacetylated glycerol fatty acid esters being most preferred. Among theglycerol fatty acid esters, the esters are, e.g., mono- or diglycerides,or mixtures of mono- and diglycerides, where the fatty acid moiety is aC₆ to C₂₂ fatty acid. In some specific embodiments, lipophilicsurfactants are selected from the products of reaction mixture ofpolyols and fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols. In more specific embodiments, polyols arepolyethylene glycol, sorbitol, propylene glycol, and pentaerythritol.

In certain embodiments, pharmaceutical compositions described hereininclude a lipophilic component or carrier. In some embodiments, thelipophilic carrier is selected from lipophilic surfactants,triglycerides, and Vitamin E compounds (e.g., d,l-a-tocopherol). Inspecific embodiments, triglycerides utilized in the pharmaceuticalcompositions described herein are those that solidify (e.g., form asolid, a semi-solid, a gel, a jelly, a paste, or the like) at ambientroom temperature, with or without addition of appropriate additives, orthose which in combination with particular surfactants and/or activeingredients solidify at room temperature. Illustrative and non-limitingexamples of triglycerides suitable for use in the pharmaceuticalcompositions described herein are shown in Table 19. In general, thesetriglycerides are readily available from commercial sources. For severaltriglycerides, representative commercial products and/or commercialsuppliers are listed.

TABLE 19 Triglycerides Triglyceride Commercial Source Aceituno oilAlmond oil Super Refined Almond Oil (Croda) Araehis oil Babassu oilBeeswax Blackcurrant seed oil Borage oil Buffalo ground oil Candlenutoil Canola oil Lipex 108 (Abitec) Castor oil Chinese vegetable tallowoil Cocoa butter Coconut oil Pureco 76 (Abitec) Coffee seed oil Corn oilSuper Refined Corn Oil (Croda) Cottonseed oil Super Refined CottonseedOil (Croda) Crambe oil Cuphea species oil Evening primrose oil Grapeseedoil Groundnut oil Hemp seed oil Illipe butter Kapok seed oil Linseed oilMenhaden oil Super Refined Menhaden Oil (Croda) Mowrah butter Mustardseed oil Oiticica oil Olive oil Super Refined Olive Oil (Croda) Palm oilPalm kernel oil Peanut oil Super Refined Peanut Oil (Croda) Poppy seedoil Rapeseed oil Rice bran oil Safflower oil Super Refined Safflower Oil(Croda) Sal fat Sesame oil Super Refined Sesame Oil (Croda) Shark liveroil Super Refined Shark Liver Oil (Croda) Shea nut oil Soybean oil SuperRefined Soybean Oil (Croda) Stillingia oil Sunflower oil Tall oil Teaseed oil Tobacco seed oil Tung oil (China wood oil) Ucuhuba Vernonia oilWheat germ oil Super Refined Wheat Germ Oil (Croda) Hydrogenated castoroil Castorwax Hydrogenated coconut oil Pureco 100 (Abitec) Hydrogenatedcottonseed oil Dritex C (Abitec) Hydrogenated palm oil Dritex PST(Abitec); Softisan 154 (Hüls) Hydrogenated soybean oil Sterotex HM NF(Abitec); Dritex S (Abitec) Hydrogenated vegetable oil Sterotex NF(Abitec); Hydrokote M (Abitec) Hydrogenated cottonseed and castorSterotex K (Abitec) oil Partially hydrogenated soybean oil Hydrokote AP5(Abitec) Partially hydrogenated soy and Apex B (Abitec) cottonseed oilGlyceryl mono-, di-, tri-behenate Compritol 888 Glycerol tributyrate(Sigma) Glyceryl tricaproate (Sigma) Glyceryl tricaprylate (Sigma)Glyceryl tricaprate Captex 1000 (Abitec) Glyceryl triundecanoate Captex8227 (Abitec) Glyceryl trilaurate (Sigma) Glyceryl trimyristate Dynasan114 (Hüls) Glyceryl tripalmitate Dynasan 116 (Hüls) Glyceryl tristearateDynasan 118 (Hüls) Glyceryl triarchidate (Sigma) Glyceryltrimyristoleate (Sigma) Glyceryl tripalmitoleate (Sigma) Glyceryltrioleate (Sigma) Glyceryl trilinoleate (Sigma) Giyceryl trilinolenate(Sigma) Glyceryl tricaprylate/caprate Captex 300 (Abitec); Captex 355(Abitec); Miglyol 810 (Hüls); Miglyol 812 (Hüls) Glyceryltricaprylate/caprate/laurate Captex 350 (Abitec) Glyceryltricaprylate/caprate/linoleate Captex 810 (Abitec); Miglyol 818 (Hüls)Glyceryl tricaprylate/caprate/stearate Softisan 378 (Hüls); (Larodan)Glyceryl tricaprylate/laurate/stearate (Larodan) Glyceryl1,2-caprylate-3-linoleate (Larodan) Glyceryl 1,2-caprate-3-stearate(Larodan) Glyceryl 1,2-laurate-3-myristate (Larodan) Glyceryl1,2-myristate-3-laurate (Larodan) Glyceryl 1,3-palmitate-2-butyrate(Larodan) Glyceryl 1,3-stearate-2-caprate (Larodan) Glyceryl1,2-linoleate-3-caprylate (Larodan)

In certain embodiments, the triglycerides utilized in the pharmaceuticalcompositions described herein include fractionated triglycerides,modified triglycerides, synthetic triglycerides, and mixtures oftriglycerides are also within the scope of the invention. In specificembodiments, triglycerides include, by way of non-limiting example,vegetable oils, fish oils, animal fats, hydrogenated vegetable oils,partially hydrogenated vegetable oils, medium and long-chaintriglycerides, and structured triglycerides. It should be appreciatedthat several commercial surfactant compositions contain small tomoderate amounts of triglycerides, typically as a result of incompletereaction of a triglyceride starting material in, for example, atransesterification reaction. Such commercial surfactant compositions,while nominally referred to as “surfactants”, may be suitable to provideall or part of the triglyceride component for the compositions of thepresent invention. Examples of commercial surfactant compositionscontaining triglycerides include some members of the surfactant familiesGelucires (Gattefosse), Maisines (Gattefosse), and Imwitors (Hülls).Specific examples of these compositions are: Gelucire 44/14 (saturatedpolyglycolized glycerides); Gelucire 50/13 (saturated polyglycolizedglycerides); Gelucire 53/10 (saturated polyglycolized glycerides);Gelucire 33/01 (semi-synthetic triglycerides of C₈-C₁₈ saturated fattyacids); Gelucire 39/01 (semi-synthetic glycerides); other Gelucires,such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, or thelike; Maisine 35-I (linoleic glycerides); and Imwitor 742(capiylic/capric glycerides).

Additional Agents

The pharmaceutical compositions described herein optionally include oneor more additional agents or additives. In certain instances, suitableadditives include those that facilitate formulating a pharmaceuticalcomposition described herein as an oral dosage form and include, e.g.,coatings and capsule components. Further additives include, by way ofnon-limiting example, solubilizers, enzyme inhibitors, anti-foamingagents, antioxidants, binders, buffering agents, chelating agents,diluents, disintegrants, flavoring agents, preservatives, sweeteners,thickeners, or the like.

In some embodiments, pharmaceutical compositions provided hereinoptionally include one or more solubilizers, i.e., additives to increasethe solubility of the pharmaceutical active ingredient or othercomposition components in the solid carrier. Suitable solubilizers foruse in the compositions of the present invention include: alcohols,polyols, ethers of polyethylene glycols, amides, esters or the like.Alcohols and polyols include, by way of non-limiting example, ethanol,isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol,butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol,mannitol, transcutol, dimethyl isosorbide, polyethylene glycol,polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcelluloseand other cellulose derivatives, cyclodextrins and cyclodextrinderivatives. Ethers of polyethylene glycols include those having anaverage molecular weight of about 200 to about 6000, such as, by way ofnon-limiting example, tetrahydrofurfuryl alcohol PEG ether (glycofurol,available commercially from BASF under the trade name Tetraglycol) andmethoxy PEG (Union Carbide). Amides include, by way of non-limitingexample, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide, and polyvinylpyrrolidone. Esters include, by way ofnon-limiting example, ethyl propionate, tributylcitrate, acetyltriethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate,ethyl caprylate, ethyl butyrate, triacetin, propylene glycolmonoacetate, propylene glycol diacetate, ε-caprolactone and isomersthereof, δ-valerolactone and isomers thereof, β-butyrolactone andisomers thereof. Other solubilizers include, by way of non-limitingexample, dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)),N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethyleneglycol monoethyl ether (available from Gattefosse under the trade nameTranscutol), and water. Mixtures of solubilizers are also within thescope of the present disclosure. Except as indicated, these compoundsare readily available from standard commercial sources. In specificembodiments, solubilizers include, by way of non-limiting example,triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. In certainspecific embodiments, solubilizers include sorbitol, glycerol,triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. Theamount of solubilizer included in the pharmaceutical compositionsdescribed herein is any suitable amount.

Anti-adherents (anti-sticking agents, glidants, flow promoters,lubricants) include, by way of non-limiting example, talc, magnesiumstearate, fumed silica (Carbosil, Aerosil), micronized silica (SyloidNo. FP 244, Grace U.S.A.), polyethylene glycols, surfactants, waxes,stearic acid, stearic acid salts, stearic acid derivatives, starch,hydrogenated vegetable oils, sodium benzoate, sodium acetate, leucine,PEG-4000 and magnesium lauryl sulfate. Antioxidants include, by way ofnon-limiting example, BHT, BHA, gallic acid, propyl gallate, ascorbicacid, ascorbyl palmitate, 4-hydroxymethyl-2,6-di-tert-butyl phenol, andtocopherol. Binders (adhesives), i.e., agents that impart cohesiveproperties to powdered materials through particle-particle bonding,include, by way of non-limiting example, matrix binders (dry starch, drysugars), film binders (PVP, starch paste, celluloses, bentonite,sucrose), and chemical binders (polymeric cellulose derivatives, such ascarboxy methyl cellulose, HPC and HPMC; sugar syrups; corn syrup; watersoluble polysaccharides such as acacia, tragacanth, guar and alginates;gelatin; gelatin hydrolysate; agar; sucrose; dextrose; andnon-cellulosic binders, such as PVP, PEG, vinyl pyrrolidone copolymers,pregelatinized starch, sorbitol, and glucose). Buffering agents, includean acid and a base, wherein the acid is a pharmaceutically acceptableacid, such as hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid,acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, aminoacids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonicacid, citric acid, fatty acids, formic acid, fumaric acid, gluconicacid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleicacid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid,propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid,succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid and uric acid, and the base is a pharmaceuticallyacceptable base, such as an amino acid, an amino acid ester, ammoniumhydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide,magnesium aluminum silicate, synthetic aluminum silicate, synthetichydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine,ethanolamine, ethylenediamine, triethanolamine, triethylamine,triisopropanolamine, or a salt of a pharmaceutically acceptable cationand acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, an amino acid, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, a fatty acid, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, and uric acid. Chelating agentsinclude, by way of non-limiting example, EDTA and EDTA salts. Colorantsor opaquants include, by way of non-limiting example, titanium dioxide,food dyes, lakes, natural vegetable colorants, iron oxides, silicates,sulfates, magnesium hydroxide and aluminum hydroxide. Diluents orfillers include, by way of non-limiting example, lactose, mannitol,talc, magnesium stearate, sodium chloride, potassium chloride, citricacid, spray-dried lactose, hydrolyzed starches, directly compressiblestarch, microcrystalline cellulose, cellulosics, sorbitol, sucrose,sucrose-based materials, calcium sulfate, dibasic calcium phosphate anddextrose. Disintegrants and super disintegrants include, by way ofnon-limiting example, croscarmellose sodium, starch, starch derivatives,clays, gums, cellulose, cellulose derivatives, alginates, crosslinkedpolyvinypyrrolidone, sodium starch glycolate and microcrystallinecellulose. Flavorants or desensitizers include, by way of non-limitingexample, spray-dried flavors, essential oils and ethyl vanillin.Plasticizers include, by way of non-limiting example, polyethyleneglycol, citrate esters (e.g., triethyl citrate, acetyl triethyl citrate,acetyltributyl citrate), acetylated monoglycerides, glycerin, triacetin,propylene glycol, phthalate esters (e.g., diethyl phthalate, dibutylphthalate), castor oil, sorbitol and dibutyl seccate. Preservativesinclude, by way of non-limiting example, ascorbic acid, boric acid,sorbic acid, benzoic acid, and salts thereof, parabens, phenols, benzylalcohol, and quaternary ammonium compounds. Solvents include, by way ofnon-limiting example, alcohols, ketones, esters, chlorinatedhydrocarbons and water. Sweeteners include, by way of non-limitingexample, natural sweeteners such as maltose, sucrose, glucose, sorbitol,glycerin and dextrins, and artificial sweeteners, such as aspartame,saccharine and saccharine salts. Thickeners (viscosity modifiers,thickening agents) include, by way of non-limiting example, sugars,polyvinylpyrrolidone, cellulosics, polymers, high molecular weightpolyethylene glycols (e.g., PEG 8000), and alginates. Additives alsoinclude, by way of non-limiting example, proteins (e.g., collagen,gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates(e.g., alginates, carrageenan, cellulose derivatives, pectin, starch,chitosan); gums (e.g., xanthan gum, gum arabic); spermaceti; natural orsynthetic waxes; carnauba wax; fatty acids (e.g., stearic acid,hydroxystearic acid); fatty alcohols; sugars; shellacs, such as thosebased on sugars (e.g., lactose, sucrose, dextrose) or starches;polysaccharide-based shellacs (e.g., maltodextrin and maltodextrinderivatives, dextrates, cyclodextrin and cyclodextrin derivatives);cellulosic-based shellacs (e.g., microcrystalline cellulose, sodiumcarboxymethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose,hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, celluloseacetate butyrate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropylmethyl cellulose phthalate); inorganics, such asdicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc andtitania; polyols, such as mannitol, xylitol and sorbitol; polyethyleneglycol esters; and polymers, such as alginates, poly(lactidecoglycolide), gelatin, crosslinked gelatin, and agar-agar.

It should be appreciated that there is considerable overlap between theabove-listed additives in common usage, since a given additive is oftenclassified differently by different practitioners in the field, or iscommonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in compositionsof the present invention. The amounts of such additives can be readilydetermined by one skilled in the art, according to the particularproperties desired.

Dosage Forms

In various embodiments, pharmaceutical compositions described herein areformulated as oral dosage forms. Oral dosage forms are prepared by anysuitable process including one or more steps of, by way of non-limitingexample, agglomeration, air suspension chilling, air suspension drying,balling, coacervation, comminution, compression, pelletization,cryopelletization, encapsulation, extrusion, granulation,homogenization, inclusion complexation, lyophilization,nanoencapsulation, melting, mixing, molding, pan coating, solventdehydration, sonication, spheronization, spray chilling, spraycongealing, spray drying, or the like.

In some embodiments, a pharmaceutical composition described herein isformulated with a substrate to form an oral dosage form. In variousembodiments, substrates useful for formulating pharmaceuticalcompositions described herein as oral dosage forms include or comprise,by way of non-limiting example, a powder or a multiparticulate (e.g.,one or more granule, one or more pellet, one or more bead, one or morespherule, one or more beadlet, one or more microcapsule, one or moremillisphere, one or more mini capsule, one or more microcapsule, one ormore nanocapsule, one or more nanosphere, one or more microsphere, oneor more minitablet, one or more tablet, one or more capsule, or one ormore combinations thereof). In certain instances, a powder constitutes afinely divided (milled, micronized, nanosized, precipitated) form of anactive ingredient or additive molecular aggregates or a compoundaggregate of multiple components or a physical mixture of aggregates ofan active ingredient and/or additives.

Substrates are prepared from any suitable material including, by way ofnon-limiting example, sugars, such as lactose, sucrose or dextrose;polysaccharides, such as maltodextrin or dextrates; starches;cellulosics, such as microcrystalline cellulose or microcrystallinecellulose/sodium carboxymethyl cellulose; inorganics, such as dicalciumphosphate, hydroxyapitite, tricalcium phosphate, talc, or titania; andpolyols, such as mannitol, xylitol, sorbitol or cyclodextrin.Furthermore, the substrate is optionally composed of active ingredients,surfactants, triglycerides or additives described herein. In oneparticular embodiment, the substrate is a solid form of an additive, anactive ingredient, a surfactant, or a triglyceride; a complex of anadditive, surfactant or triglyceride and an active ingredient; acoprecipitate of an additive, surfactant or triglyceride and an activeingredient, or a mixture thereof.

In various embodiments, pharmaceutical compositions and substratesdescribed herein provide or are formulated to provide an oral dosagefrom selected from, by way of non-limiting example, a minicapsule, acapsule, a tablet, an implant, a troche, a lozenge (minitablet), atemporary or permanent suspension, a wafer, a chewable tablet, a quickor fast dissolving tablet, an effervescent tablet, a buccal orsublingual solid, a granule, a film, a sprinkle, a pellet, a bead, apill, a powder, a triturate, a strip or a sachet.

In specific embodiments, the oral dosage form described herein is acapsule. Suitable capsule forms include, by way of non-limiting example,hard or soft gelatin capsules, starch capsules, and cellulosic capsules.In more specific embodiments, oral dosage forms described herein are inthe form of hard or soft gelatin capsules. In some embodiments, the oraldosage form is a capsule comprising a jelly, solid, semi-solid, glassyor paste-like composition, wherein the testosterone alkyl ester isformulated into the composition.

In specific embodiments, a pharmaceutical composition described hereinis formulated as an oral dosage form by (i) heating a pharmaceuticalcompositions described herein until pharmaceutical composition has anability to flow (e.g., it is a homogeneous solution, an emulsion, aslurry or the like); and (ii) depositing the pharmaceutical compositionwith an ability to flow on a substrate. In more specific embodiments,the pharmaceutical composition that has an ability to flow is ahomogeneous solution. In further or alternative embodiments, thesubstrate is one or more capsule, one or more microcapsule, or one ormore nanocapsule. In more specific embodiments, the substrate is a hardgelatin capsule or a soft gelatin capsule. In still more specificembodiments, the substrate is a hard gelatin capsule.

EXAMPLES Example 1

In certain instances, oral dosage forms are prepared in the followingmanner:

Step 1: transfer the selected amounts of carriers and additives into aclean container and heat the combination until a molten solution isobtained;

Step 2: transfer the selected amount of steroidal compound (e.g.,testosterone undecanoate) to the molten solution obtained in Step 1 andhomogenize;

Step 3: maintain the mixture of Step 2 at an elevated temperature untilused in Step 4; and

Step 4: encapsulation of the mixture of Step 3 (e.g., in a hard gelatincapsule).

Using the preceding process, the following capsules are prepared:

TABLE 20 Capsule 1 Component % w/w Testosterone undecanoate 15 Polyoxyl40 Hydrogenated Castor Oil, NF 16 Glyceryl Monolinoleate, NF (Maisine35-1) 63 Polyethylene Glycol 8000, USP 6 Total 100

TABLE 21 Capsule 2 Component % w/w Testosterone undecanoate 25 Polyoxyl35 Castor Oil, NF 21 Vitamin E, USP (d,l-α-tocopherol) 48 PolyethyleneGlycol 8000, USP 6 Total 100

TABLE 22 Capsule 3 Component % w/w Testosterone undecanoate 22 Vitamin EPolyethylene Glycol Succinate, NF 22 Vitamin E, USP (d,l-tocopherol) 34Polyethylene Glycol 8000, USP 4 Hypromellose (100 cP, K100 Premium LV)18 Total 100

TABLE 23 Capsule 4 Component % w/w Testosterone undecanoate 22 Vitamin EPolyethylene Glycol Succinate, NF 22 Vitamin E, USP (d,l-tocopherol) 34Polyethylene Glycol 8000, USP 4 Hypromellose (4,000 cP, K4M) 18 Total100

Example 2

Capsules 1-4 are subjected to USP Type-II (paddle) apparatus conditionsat 37±0.5° C., at 100 rpm (i.e., deposited in 1 L of DI water having 8%w/v of Triton X-100). FIG. 1 illustrates the release profiles ofCapsules 1-4.

Example 3

Clinical Trial Protocol

Study Population: Healthy volunteers (N=24) with a BMI of 18-30 kg/m²and having a pre-trial screening total T concentration of less than 1.3ng/mL (4.5 nmol/L). Healthy volunteers include post-menopausal womenaged 45 or greater.

Study Design: Phase-I, single center, randomized, open-label, study ofCapsules 1-4 and 3× an immediate release oral dosage form comprising 40mg of testosterone undecanoate (so as to provide the same 120 mg dose asCapsules 1-4) formulated in a mixture of castor oil and propylene glycollaurate available under the tradename ANDRIOL.

Mode of administration: Orally with 240 mL of water about 30 minutesafter starting a standardized, high fat, high calorie breakfast precededby a 10 hour fast. Duration between treatments: minimum of 7 daysbetween the start of each treatment period.

FIG. 2 illustrates the mean plasma testosterone concentrations followingadministration of Capsules 1-4 and 3× a 40 mg immediate release oraldosage form (for a total of a 120 mg immediate release dose). FIG. 3illustrates the mean plasma testosterone undecanoate concentrationsfollowing administration of Capsules 1-4 and 3× a 40 mg immediaterelease oral dosage form (for a total of a 120 mg immediate releasedose). FIG. 4 illustrates the mean plasma dihydrotestosteroneconcentrations following administration of Capsules 1-4 and 3× a 40 mgimmediate release oral dosage form (for a total of a 120 mg immediaterelease dose).

Tables 24-26 illustrate the concentration levels of singleadministration and simulated steady state levels of testosterone,testosterone undecanoate, and dihydrotestosterone obtained.

TABLE 24 Mean Plasma Testosterone Levels Capsule Capsule Capsule Capsule1 2 3 4 IR Mean C_(max) (ng/mL) single 18.2 13.6 7.5 8.8 19.7 dose MeanC_(max) (ng/mL) steady 17.0 13.1 6.7 8.6 15.7 state Mean C_(min) (ng/mL)steady 0.35 2.3 1.0 1.4 3.4 state

TABLE 25 Mean Plasma Testosterone Undecanoate Levels Capsule CapsuleCapsule Capsule 1 2 3 4 IR Mean C_(max) (ng/mL) single 384.8 264.0 126.9156.1 407.8 dose Mean C_(max) (ng/mL) steady 260.1 187.1 78.7 111.5240.8 state Mean C_(min) (ng/mL) steady 15.0 8.9 1.1 1.8 9.6 state

TABLE 26 Mean Plasma Dihydrotestosterone Levels Capsule Capsule CapsuleCapsule 1 2 3 4 IR Mean C_(max) (ng/mL) single 4.4 3.6 2.3 2.4 3.9 doseMean C_(max) (ng/mL) steady 4.6 4.0 2.3 2.3 4.1 state Mean C_(min)(ng/mL) steady 2.2 1.6 0.9 1.0 2.2 state

What is claimed is:
 1. A method of treating a hypogonadal malecomprising orally administering to the male twice-daily a compositioncomprising a capsule and a semi-solid formulation encased within thecapsule, the formulation comprising: a) 20-25 percent by weight oftestosterone undecanoate (TU), b) 10-21 percent by weight of hydrophilicsurfactant, and c) 48-70 percent by weight of lipophilic carrierselected from lipophilic surfactant, triglycerides, or Vitamin Ecompounds, wherein the formulation in the capsule administered twicedaily comprises about 120 mg to about 400 mg of TU, and wherein thecomposition, when orally administered to a plurality of hypogonadalmales provides, a mean plasma concentration of testosterone at steadystate of between 300 ng/dL and 1000 ng/dL in at least 75% of the males,a plasma C_(max) concentration of testosterone less than 1800 ng/dL inat least 95% of males, less than 1500 ng/dL in at least 85% of males,and less than 2500 ng/dL in all males.
 2. The method of claim 1, whereinadministration of the composition provides a serum T_(max) at 3 to 9hours.
 3. The method of claim 1, wherein the formulation furthercomprises a 5-alpha reductase inhibitor.
 4. The method of claim 1,wherein the formulation further comprises a digestible oil.
 5. Themethod of claim 4, wherein the hydrophilic surfactant is polyoxyethylene(40) hydrogenated castor oil and the lipophilic surfactant is oleicacid.
 6. The method of claim 1, wherein the composition releases about40 wt. % TU within the first 30 minutes and about 60 wt. % TU after 4hours in an aqueous medium.
 7. The method of claim 1, wherein theformulation in the capsule administered twice daily comprises about 120mg to about 240 mg of TU.